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1. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

Author

Dareng EO, Coetzee SG, Tyrer JP, Peng PC, Rosenow W, Chen S, Davis BD, Dezem FS, Seo JH, Nameki R, Reyes AL, Aben KKH, Anton-Culver H, Antonenkova NN, Aravantinos G, Bandera EV, Beane Freeman LE, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bernardini MQ, Bjorge L, Black A, Bogdanova NV, Bolton KL, Brenton JD, Budzilowska A, Butzow R, Cai H, Campbell I, Cannioto R, Chang-Claude J, Chanock SJ, Chen K, Chenevix-Trench G, Chiew YE, Cook LS, DeFazio A, Dennis J, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles DM, Ene G, Fasching PA, Flanagan JM, Fortner RT, Fostira F, Gentry-Maharaj A, Giles GG, Goodman MT, Gronwald J, Haiman CA, Håkansson N, Heitz F, Hildebrandt MAT, Høgdall E, Høgdall CK, Huang RY, Jensen A, Jones ME, Kang D, Karlan BY, Karnezis AN, Kelemen LE, Kennedy CJ, Khusnutdinova EK, Kiemeney LA, Kjaer SK, Kupryjanczyk J, Labrie M, Lambrechts D, Larson MC, Le ND, Lester J, Li L, Lubiński J, Lush M, Marks JR, Matsuo K, May T, McLaughlin JR, McNeish IA, Menon U, Missmer S, Modugno F, Moffitt M, Monteiro AN, Moysich KB, Narod SA, Nguyen-Dumont T, Odunsi K, Olsson H, Onland-Moret NC, Park SK, Pejovic T, Permuth JB, Piskorz A, Prokofyeva D, Riggan MJ, Risch HA, Rodríguez-Antona C, Rossing MA, Sandler DP, Setiawan VW, Shan K, Song H, Southey MC, Steed H, Sutphen R, Swerdlow AJ, Teo SH, Terry KL, Thompson PJ, Vestrheim Thomsen LC, Titus L, Trabert B, Travis R, Tworoger SS, Valen E, Van Nieuwenhuysen E, Edwards DV, Vierkant RA, Webb PM, Weinberg CR, Weise RM, Wentzensen N, White E, Winham SJ, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Zeinomar N, Zheng W, Ziogas A, Berchuck A, Goode EL, Huntsman DG, Pearce CL, Ramus SJ, Sellers TA, Freedman ML, Lawrenson K, Schildkraut JM, Hazelett D, Plummer JT, Kar S, Jones MR, Pharoah PDP, and Gayther SA

Subjects
Humans, Female, Carcinoma, Ovarian Epithelial genetics, Transcriptome, Risk Factors, Genomics methods, Case-Control Studies, Multiomics, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Genetic Predisposition to Disease
Abstract

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10 -8 ) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10 -5 ). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2024
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2. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.

Author

O'Mahony DG, Ramus SJ, Southey MC, Meagher NS, Hadjisavvas A, John EM, Hamann U, Imyanitov EN, Andrulis IL, Sharma P, Daly MB, Hake CR, Weitzel JN, Jakubowska A, Godwin AK, Arason A, Bane A, Simard J, Soucy P, Caligo MA, Mai PL, Claes KBM, Teixeira MR, Chung WK, Lazaro C, Hulick PJ, Toland AE, Pedersen IS, Neuhausen SL, Vega A, de la Hoya M, Nevanlinna H, Dhawan M, Zampiga V, Danesi R, Varesco L, Gismondi V, Vellone VG, James PA, Janavicius R, Nikitina-Zake L, Nielsen FC, van Overeem Hansen T, Pejovic T, Borg A, Rantala J, Offit K, Montagna M, Nathanson KL, Domchek SM, Osorio A, García MJ, Karlan BY, De Fazio A, Bowtell D, McGuffog L, Leslie G, Parsons MT, Dörk T, Speith LM, Dos Santos ES, da Costa AABA, Radice P, Peterlongo P, Papi L, Engel C, Hahnen E, Schmutzler RK, Wappenschmidt B, Easton DF, Tischkowitz M, Singer CF, Tan YY, Whittemore AS, Sieh W, Brenton JD, Yannoukakos D, Fostira F, Konstantopoulou I, Soukupova J, Vocka M, Chenevix-Trench G, Pharoah PDP, Antoniou AC, Goldgar DE, Spurdle AB, and Michailidou K

Subjects
Humans, Female, Virulence, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics, Breast Neoplasms
Abstract

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system., Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong)., Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis., Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management., (© 2023. The Author(s).)

Published
2023
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3. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants.

Author

Li S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, Nielsen HR, Lee A, Yang X, McGuffog L, Parsons MT, Andrulis IL, Arnold N, Belotti M, Borg Å, Buecher B, Buys SS, Caputo SM, Chung WK, Colas C, Colonna SV, Cook J, Daly MB, de la Hoya M, de Pauw A, Delhomelle H, Eason J, Engel C, Evans DG, Faust U, Fehm TN, Fostira F, Fountzilas G, Frone M, Garcia-Barberan V, Garre P, Gauthier-Villars M, Gehrig A, Glendon G, Goldgar DE, Golmard L, Greene MH, Hahnen E, Hamann U, Hanson H, Hassan T, Hentschel J, Horvath J, Izatt L, Janavicius R, Jiao Y, John EM, Karlan BY, Kim SW, Konstantopoulou I, Kwong A, Laugé A, Lee JW, Lesueur F, Mebirouk N, Meindl A, Mouret-Fourme E, Musgrave H, Ngeow Yuen Yie J, Niederacher D, Park SK, Pedersen IS, Ramser J, Ramus SJ, Rantala J, Rashid MU, Reichl F, Ritter J, Rump A, Santamariña M, Saule C, Schmidt G, Schmutzler RK, Senter L, Shariff S, Singer CF, Southey MC, Stoppa-Lyonnet D, Sutter C, Tan Y, Teo SH, Terry MB, Thomassen M, Tischkowitz M, Toland AE, Torres D, Vega A, Wagner SA, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Spurdle AB, Easton DF, Chenevix-Trench G, Ottini L, and Antoniou AC

Subjects
BRCA1 Protein genetics, BRCA2 Protein genetics, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Risk, Breast Neoplasms, Breast Neoplasms, Male, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics
Abstract

Purpose: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management., Methods: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment., Results: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers., Conclusion: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs., Competing Interests: Timothy R. RebbeckHonoraria: AstraZeneca (I)Consulting or Advisory Role: AstraZeneca (I) Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise. Norbert ArnoldHonoraria: AstraZeneca Åke BorgHonoraria: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, AstraZeneca Sandrine CaputoResearch Funding: AstraZeneca/France (Inst) Wendy K. ChungConsulting or Advisory Role: RegeneronResearch Funding: Biogen Chrystelle ColasConsulting or Advisory Role: AstraZeneca/Merck, Pfizer Miguel de la HoyaConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca D. Gareth EvansHonoraria: AstraZeneca Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche George FountzilasStock and Other Ownership Interests: GENPREX Inc (I), ARIAD (I), Deciphera Pharmaceuticals Inc (I), Daiichi Sankyo, RFL Holdings, FORMYCONHonoraria: AstraZenecaConsulting or Advisory Role: Pfizer, Roche, NovartisSpeakers' Bureau: Roche (I), LEO Pharma (I), Pfizer (I)Travel, Accommodations, Expenses: Merck (I), Pfizer (I), K.A.M Oncology/Hematology (I) Megan FronePatents, Royalties, Other Intellectual Property: Receive royalties for being a codeveloper of CancerGene Connect Eric HahnenConsulting or Advisory Role: AstraZeneca Helen HansonHonoraria: Pfizer Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy Bioanalytics, GRAILResearch Funding: GOG Foundation (Inst), NCI-NRG Oncology (Inst), Genentech/Roche (Inst)Patents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Irene KonstantopoulouSpeakers' Bureau: AstraZenecaResearch Funding: AstraZeneca Ava KwongHonoraria: Stryker, AstraZeneca Taiwan Limited, Roche Singapore, Pfizer, AstraZeneca Hong Kong Ltd Joanne Ngeow Yuen YieResearch Funding: AstraZeneca Rita K. SchmutzlerHonoraria: AstraZeneca, Clovis, MSD/AstraZenecaConsulting or Advisory Role: AstraZeneca, MSD/AstraZenecaResearch Funding: Amgen Leigha SenterConsulting or Advisory Role: AstraZeneca/MerckSpeakers' Bureau: AstraZeneca/Merck Christian F. SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Dominique Stoppa-LyonnetHonoraria: AstraZeneca/Merck (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, Roche Sebastian A. WagnerConsulting or Advisory Role: Bayer Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. May receive royalties if commercialization is realized.No other potential conflicts of interest were reported.

Published
2022
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4. Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Author

Dareng EO, Tyrer JP, Barnes DR, Jones MR, Yang X, Aben KKH, Adank MA, Agata S, Andrulis IL, Anton-Culver H, Antonenkova NN, Aravantinos G, Arun BK, Augustinsson A, Balmaña J, Bandera EV, Barkardottir RB, Barrowdale D, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Bjorge L, Black A, Bogdanova NV, Bonanni B, Borg A, Brenton JD, Budzilowska A, Butzow R, Buys SS, Cai H, Caligo MA, Campbell I, Cannioto R, Cassingham H, Chang-Claude J, Chanock SJ, Chen K, Chiew YE, Chung WK, Claes KBM, Colonna S, Cook LS, Couch FJ, Daly MB, Dao F, Davies E, de la Hoya M, de Putter R, Dennis J, DePersia A, Devilee P, Diez O, Ding YC, Doherty JA, Domchek SM, Dörk T, du Bois A, Dürst M, Eccles DM, Eliassen HA, Engel C, Evans GD, Fasching PA, Flanagan JM, Fortner RT, Machackova E, Friedman E, Ganz PA, Garber J, Gensini F, Giles GG, Glendon G, Godwin AK, Goodman MT, Greene MH, Gronwald J, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TVO, Harris HR, Hartman M, Heitz F, Hildebrandt MAT, Høgdall E, Høgdall CK, Hopper JL, Huang RY, Huff C, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James PA, Janavicius R, Jensen A, Johannsson OT, John EM, Jones ME, Kang D, Karlan BY, Karnezis A, Kelemen LE, Khusnutdinova E, Kiemeney LA, Kim BG, Kjaer SK, Komenaka I, Kupryjanczyk J, Kurian AW, Kwong A, Lambrechts D, Larson MC, Lazaro C, Le ND, Leslie G, Lester J, Lesueur F, Levine DA, Li L, Li J, Loud JT, Lu KH, Lubiński J, Mai PL, Manoukian S, Marks JR, Matsuno RK, Matsuo K, May T, McGuffog L, McLaughlin JR, McNeish IA, Mebirouk N, Menon U, Miller A, Milne RL, Minlikeeva A, Modugno F, Montagna M, Moysich KB, Munro E, Nathanson KL, Neuhausen SL, Nevanlinna H, Yie JNY, Nielsen HR, Nielsen FC, Nikitina-Zake L, Odunsi K, Offit K, Olah E, Olbrecht S, Olopade OI, Olson SH, Olsson H, Osorio A, Papi L, Park SK, Parsons MT, Pathak H, Pedersen IS, Peixoto A, Pejovic T, Perez-Segura P, Permuth JB, Peshkin B, Peterlongo P, Piskorz A, Prokofyeva D, Radice P, Rantala J, Riggan MJ, Risch HA, Rodriguez-Antona C, Ross E, Rossing MA, Runnebaum I, Sandler DP, Santamariña M, Soucy P, Schmutzler RK, Setiawan VW, Shan K, Sieh W, Simard J, Singer CF, Sokolenko AP, Song H, Southey MC, Steed H, Stoppa-Lyonnet D, Sutphen R, Swerdlow AJ, Tan YY, Teixeira MR, Teo SH, Terry KL, Terry MB, Thomassen M, Thompson PJ, Thomsen LCV, Thull DL, Tischkowitz M, Titus L, Toland AE, Torres D, Trabert B, Travis R, Tung N, Tworoger SS, Valen E, van Altena AM, van der Hout AH, Van Nieuwenhuysen E, van Rensburg EJ, Vega A, Edwards DV, Vierkant RA, Wang F, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, White E, Whittemore AS, Winham SJ, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Zavaglia KM, Zheng W, Ziogas A, Zorn KK, Kleibl Z, Easton D, Lawrenson K, DeFazio A, Sellers TA, Ramus SJ, Pearce CL, Monteiro AN, Cunningham J, Goode EL, Schildkraut JM, Berchuck A, Chenevix-Trench G, Gayther SA, Antoniou AC, and Pharoah PDP

Subjects
Bayes Theorem, Carcinoma, Ovarian Epithelial genetics, Female, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Breast Neoplasms, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
Abstract

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs., (© 2021. The Author(s).)

Published
2022
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5. Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.

Author

Li H, Engel C, de la Hoya M, Peterlongo P, Yannoukakos D, Livraghi L, Radice P, Thomassen M, Hansen TVO, Gerdes AM, Nielsen HR, Caputo SM, Zambelli A, Borg A, Solano A, Thomas A, Parsons MT, Antoniou AC, Leslie G, Yang X, Chenevix-Trench G, Caldes T, Kwong A, Pedersen IS, Lautrup CK, John EM, Terry MB, Hopper JL, Southey MC, Andrulis IL, Tischkowitz M, Janavicius R, Boonen SE, Kroeldrup L, Varesco L, Hamann U, Vega A, Palmero EI, Garber J, Montagna M, Van Asperen CJ, Foretova L, Greene MH, Selkirk T, Moller P, Toland AE, Domchek SM, James PA, Thorne H, Eccles DM, Nielsen SM, Manoukian S, Pasini B, Caligo MA, Lazaro C, Kirk J, Wappenschmidt B, Spurdle AB, Couch FJ, Schmutzler R, and Goldgar DE

Subjects
BRCA1 Protein genetics, BRCA2 Protein genetics, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Genetic Testing methods, Germ-Line Mutation genetics, Humans, Middle Aged, Breast Neoplasms genetics, Breast Neoplasms pathology, Ovarian Neoplasms genetics
Abstract

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants., Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis., Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs., Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes., Competing Interests: Conflict of Interest F.J.C. has received consulting fees from Astrazeneca. A.S. has received consulting fees from Pfizer and Astra Zeneca. T.V.O.H. has received honoraria from Pfizer. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Published
2022
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6. When cascade testing for familial variant seems inadequate to provide clinically actionable information for blood relatives.

Author

Apostolou P, Fostira F, Fountzilas G, Razis E, Yannoukakos D, and Konstantopoulou I

Subjects
Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Ovarian Neoplasms pathology, Prognosis, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Family, Genetic Carrier Screening standards, Genetic Testing standards, Mutation, Ovarian Neoplasms genetics
Abstract

Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest.

Published
2021
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7. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Author

Glubb DM, Thompson DJ, Aben KKH, Alsulimani A, Amant F, Annibali D, Attia J, Barricarte A, Beckmann MW, Berchuck A, Bermisheva M, Bernardini MQ, Bischof K, Bjorge L, Bodelon C, Brand AH, Brenton JD, Brinton LA, Bruinsma F, Buchanan DD, Burghaus S, Butzow R, Cai H, Carney ME, Chanock SJ, Chen C, Chen XQ, Chen Z, Cook LS, Cunningham JM, De Vivo I, deFazio A, Doherty JA, Dörk T, du Bois A, Dunning AM, Dürst M, Edwards T, Edwards RP, Ekici AB, Ewing A, Fasching PA, Ferguson S, Flanagan JM, Fostira F, Fountzilas G, Friedenreich CM, Gao B, Gaudet MM, Gawełko J, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harris HR, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Høgdall E, Høgdall CK, Holliday EG, Huntsman DG, Huzarski T, Jakubowska A, Jensen A, Jones ME, Karlan BY, Karnezis A, Kelley JL, Khusnutdinova E, Killeen JL, Kjaer SK, Klapdor R, Köbel M, Konopka B, Konstantopoulou I, Kopperud RK, Koti M, Kraft P, Kupryjanczyk J, Lambrechts D, Larson MC, Le Marchand L, Lele S, Lester J, Li AJ, Liang D, Liebrich C, Lipworth L, Lissowska J, Lu L, Lu KH, Macciotta A, Mattiello A, May T, McAlpine JN, McGuire V, McNeish IA, Menon U, Modugno F, Moysich KB, Nevanlinna H, Odunsi K, Olsson H, Orsulic S, Osorio A, Palli D, Park-Simon TW, Pearce CL, Pejovic T, Permuth JB, Podgorska A, Ramus SJ, Rebbeck TR, Riggan MJ, Risch HA, Rothstein JH, Runnebaum IB, Scott RJ, Sellers TA, Senz J, Setiawan VW, Siddiqui N, Sieh W, Spiewankiewicz B, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Thompson PJ, Thomsen LCV, Titus L, Tone A, Tumino R, Turman C, Vanderstichele A, Edwards DV, Vergote I, Vierkant RA, Wang Z, Wang-Gohrke S, Webb PM, White E, Whittemore AS, Winham SJ, Wu X, Wu AH, Yannoukakos D, Spurdle AB, and O'Mara TA

Subjects
Carcinoma, Ovarian Epithelial genetics, Female, Genome-Wide Association Study, Humans, Quantitative Trait Loci genetics, Risk Factors, Endometrial Neoplasms genetics, Ovarian Neoplasms genetics
Abstract

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers., Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data., Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 -5 ). We found seven loci associated with risk for both cancers ( P Bonferroni < 2.4 × 10 -9 ). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10 -7 ). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation., Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis., Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings., (©2020 American Association for Cancer Research.)

Published
2021
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8. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Author

Barnes DR, Rookus MA, McGuffog L, Leslie G, Mooij TM, Dennis J, Mavaddat N, Adlard J, Ahmed M, Aittomäki K, Andrieu N, Andrulis IL, Arnold N, Arun BK, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Benitez J, Berthet P, Białkowska K, Blanco AM, Blok MJ, Bonanni B, Boonen SE, Borg Å, Bozsik A, Bradbury AR, Brennan P, Brewer C, Brunet J, Buys SS, Caldés T, Caligo MA, Campbell I, Christensen LL, Chung WK, Claes KBM, Colas C, Collonge-Rame MA, Cook J, Daly MB, Davidson R, de la Hoya M, de Putter R, Delnatte C, Devilee P, Diez O, Ding YC, Domchek SM, Dorfling CM, Dumont M, Eeles R, Ejlertsen B, Engel C, Evans DG, Faivre L, Foretova L, Fostira F, Friedlander M, Friedman E, Frost D, Ganz PA, Garber J, Gehrig A, Gerdes AM, Gesta P, Giraud S, Glendon G, Godwin AK, Goldgar DE, González-Neira A, Greene MH, Gschwantler-Kaulich D, Hahnen E, Hamann U, Hanson H, Hentschel J, Hogervorst FBL, Hooning MJ, Horvath J, Hu C, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James PA, Janavicius R, John EM, Joseph V, Karlan BY, Kast K, Koudijs M, Kruse TA, Kwong A, Laitman Y, Lasset C, Lazaro C, Lester J, Lesueur F, Liljegren A, Loud JT, Lubiński J, Mai PL, Manoukian S, Mari V, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller A, Montagna M, Mouret-Fourme E, Mukherjee S, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Niederacher D, Nielsen FC, Nikitina-Zake L, Noguès C, Olah E, Olopade OI, Ong KR, O'Shaughnessy-Kirwan A, Osorio A, Ott CE, Papi L, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Peterlongo P, Pfeiler G, Phillips KA, Prajzendanc K, Pujana MA, Radice P, Ramser J, Ramus SJ, Rantala J, Rennert G, Risch HA, Robson M, Rønlund K, Salani R, Schuster H, Senter L, Shah PD, Sharma P, Side LE, Singer CF, Slavin TP, Soucy P, Southey MC, Spurdle AB, Steinemann D, Steinsnyder Z, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teo SH, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Trainer AH, Tung N, van Engelen K, van Rensburg EJ, Vega A, Vierstraete J, Wagner G, Walker L, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Yadav S, Yang X, Yannoukakos D, Zimbalatti D, Offit K, Thomassen M, Couch FJ, Schmutzler RK, Simard J, Easton DF, Chenevix-Trench G, and Antoniou AC

Subjects
BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial genetics, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Prospective Studies, Retrospective Studies, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
Abstract

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers., Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort., Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 -72 ). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 -50 ). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 -22 ) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 -12 ) carriers. The associations in the prospective cohort were similar., Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Published
2020
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9. Prevalence and founder effect of the BRCA1 p.(Val1833Met) variant in the Greek population, with further evidence for pathogenicity and risk modification.

Author

Papamentzelopoulou M, Apostolou P, Fostira F, Dimitrakakis C, Loutradis D, Fountzilas G, Yannoukakos D, and Konstantopoulou I

Subjects
Female, Greece epidemiology, Humans, Likelihood Functions, Ovarian Neoplasms genetics, Prevalence, Founder Effect, Genes, BRCA1, Genetic Predisposition to Disease, Ovarian Neoplasms epidemiology
Abstract

Purpose: Multiple lines of evidence have suggested a likely causative role in breast/ovarian cancer (BrCa/OvCa) predisposition for the BRCA1 p.(Val1833Met) variant, predominantly found among Greek patients. Our aim was to study the variant's prevalence and founder effect on the Greek population, while providing additional data for its pathogenicity., Methods: We genotyped 3531 BrCa/OvCa patients using Sanger and next generation sequencing, as well as 1558 healthy, age-matched females with real-time PCR. Carriers underwent haplotype analysis to determine a founder effect. A co-segregation analysis was applied to estimate the likelihood ratio for pathogenicity., Results: In total, 27 BrCa/OvCa patients (0.77%; 27/3531) were found to carry the p.(Val1833Met) variant. No carriers were identified in the control group diagnosis. A common shared haplotype, spanning 2.76 Mb on chromosome 17 was demonstrated among carriers, establishing the founder effect. BRCA1, p.(Val1833Met) is possibly a disease-associated variant, supported by a likelihood ratio of 1.88, while a correlation to ovarian cancer is suspected., Conclusions: Altogether, BRCA1, p.(Val1833Met) variant is a Greek founder and is very likely to predispose for BrCa/OvCa. Therefore, such carriers should be counselled accordingly, with clinical recommendations supporting surveillance and risk-reduction strategies, while providing the option for targeted therapeutic interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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10. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

Author

Qian F, Rookus MA, Leslie G, Risch HA, Greene MH, Aalfs CM, Adank MA, Adlard J, Agnarsson BA, Ahmed M, Aittomäki K, Andrulis IL, Arnold N, Arun BK, Ausems MGEM, Azzollini J, Barrowdale D, Barwell J, Benitez J, Białkowska K, Bonadona V, Borde J, Borg A, Bradbury AR, Brunet J, Buys SS, Caldés T, Caligo MA, Campbell I, Carter J, Chiquette J, Chung WK, Claes KBM, Collée JM, Collonge-Rame MA, Couch FJ, Daly MB, Delnatte C, Diez O, Domchek SM, Dorfling CM, Eason J, Easton DF, Eeles R, Engel C, Evans DG, Faivre L, Feliubadaló L, Foretova L, Friedman E, Frost D, Ganz PA, Garber J, Garcia-Barberan V, Gehrig A, Glendon G, Godwin AK, Gómez Garcia EB, Hamann U, Hauke J, Hopper JL, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Jakubowska A, Janavicius R, John EM, Karlan BY, Kets CM, Laitman Y, Lázaro C, Leroux D, Lester J, Lesueur F, Loud JT, Lubiński J, Łukomska A, McGuffog L, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Miller A, Montagna M, Mooij TM, Mouret-Fourme E, Nathanson KL, Nehoray B, Neuhausen SL, Nevanlinna H, Nielsen FC, Offit K, Olah E, Ong KR, Oosterwijk JC, Ottini L, Parsons MT, Peterlongo P, Pfeiler G, Pradhan N, Radice P, Ramus SJ, Rantala J, Rennert G, Robson M, Rodriguez GC, Salani R, Scheuner MT, Schmutzler RK, Shah PD, Side LE, Simard J, Singer CF, Steinemann D, Stoppa-Lyonnet D, Tan YY, Teixeira MR, Terry MB, Thomassen M, Tischkowitz M, Tognazzo S, Toland AE, Tung N, van Asperen CJ, van Engelen K, van Rensburg EJ, Venat-Bouvet L, Vierstraete J, Wagner G, Walker L, Weitzel JN, Yannoukakos D, Antoniou AC, Goldgar DE, Olopade OI, Chenevix-Trench G, Rebbeck TR, and Huo D

Subjects
Adult, Aged, Female, Humans, Menopause, Middle Aged, Ovarian Neoplasms genetics, Proportional Hazards Models, Body Height, Body Mass Index, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mendelian Randomization Analysis, Mutation, Ovarian Neoplasms etiology
Abstract

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown., Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models., Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m 2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P interaction  < 0.05)., Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Published
2019
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11. Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk.

Author

Yang Y, Wu L, Shu X, Lu Y, Shu XO, Cai Q, Beeghly-Fadiel A, Li B, Ye F, Berchuck A, Anton-Culver H, Banerjee S, Benitez J, Bjørge L, Brenton JD, Butzow R, Campbell IG, Chang-Claude J, Chen K, Cook LS, Cramer DW, deFazio A, Dennis J, Doherty JA, Dörk T, Eccles DM, Edwards DV, Fasching PA, Fortner RT, Gayther SA, Giles GG, Glasspool RM, Goode EL, Goodman MT, Gronwald J, Harris HR, Heitz F, Hildebrandt MA, Høgdall E, Høgdall CK, Huntsman DG, Kar SP, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Koushik A, Lambrechts D, Le ND, Levine DA, Massuger LF, Matsuo K, May T, McNeish IA, Menon U, Modugno F, Monteiro AN, Moorman PG, Moysich KB, Ness RB, Nevanlinna H, Olsson H, Onland-Moret NC, Park SK, Paul J, Pearce CL, Pejovic T, Phelan CM, Pike MC, Ramus SJ, Riboli E, Rodriguez-Antona C, Romieu I, Sandler DP, Schildkraut JM, Setiawan VW, Shan K, Siddiqui N, Sieh W, Stampfer MJ, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Tworoger SS, Tyrer JP, Webb PM, Wentzensen N, White E, Willett WC, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, and Long J

Subjects
Biomarkers, Tumor genetics, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Models, Genetic, Predictive Value of Tests, Risk, Women's Health, Carcinoma, Ovarian Epithelial genetics, DNA Methylation, Ovarian Neoplasms genetics, White People genetics
Abstract

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study ( N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10 -7 . Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 , and SKAP1 . We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression., (©2018 American Association for Cancer Research.)

Published
2019
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12. Shared heritability and functional enrichment across six solid cancers.

Author

Jiang X, Finucane HK, Schumacher FR, Schmit SL, Tyrer JP, Han Y, Michailidou K, Lesseur C, Kuchenbaecker KB, Dennis J, Conti DV, Casey G, Gaudet MM, Huyghe JR, Albanes D, Aldrich MC, Andrew AS, Andrulis IL, Anton-Culver H, Antoniou AC, Antonenkova NN, Arnold SM, Aronson KJ, Arun BK, Bandera EV, Barkardottir RB, Barnes DR, Batra J, Beckmann MW, Benitez J, Benlloch S, Berchuck A, Berndt SI, Bickeböller H, Bien SA, Blomqvist C, Boccia S, Bogdanova NV, Bojesen SE, Bolla MK, Brauch H, Brenner H, Brenton JD, Brook MN, Brunet J, Brunnström H, Buchanan DD, Burwinkel B, Butzow R, Cadoni G, Caldés T, Caligo MA, Campbell I, Campbell PT, Cancel-Tassin G, Cannon-Albright L, Campa D, Caporaso N, Carvalho AL, Chan AT, Chang-Claude J, Chanock SJ, Chen C, Christiani DC, Claes KBM, Claessens F, Clements J, Collée JM, Correa MC, Couch FJ, Cox A, Cunningham JM, Cybulski C, Czene K, Daly MB, deFazio A, Devilee P, Diez O, Gago-Dominguez M, Donovan JL, Dörk T, Duell EJ, Dunning AM, Dwek M, Eccles DM, Edlund CK, Edwards DRV, Ellberg C, Evans DG, Fasching PA, Ferris RL, Liloglou T, Figueiredo JC, Fletcher O, Fortner RT, Fostira F, Franceschi S, Friedman E, Gallinger SJ, Ganz PA, Garber J, García-Sáenz JA, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, Goode EL, Goodman MT, Goodman G, Grankvist K, Greene MH, Gronberg H, Gronwald J, Guénel P, Håkansson N, Hall P, Hamann U, Hamdy FC, Hamilton RJ, Hampe J, Haugen A, Heitz F, Herrero R, Hillemanns P, Hoffmeister M, Høgdall E, Hong YC, Hopper JL, Houlston R, Hulick PJ, Hunter DJ, Huntsman DG, Idos G, Imyanitov EN, Ingles SA, Isaacs C, Jakubowska A, James P, Jenkins MA, Johansson M, Johansson M, John EM, Joshi AD, Kaneva R, Karlan BY, Kelemen LE, Kühl T, Khaw KT, Khusnutdinova E, Kibel AS, Kiemeney LA, Kim J, Kjaer SK, Knight JA, Kogevinas M, Kote-Jarai Z, Koutros S, Kristensen VN, Kupryjanczyk J, Lacko M, Lam S, Lambrechts D, Landi MT, Lazarus P, Le ND, Lee E, Lejbkowicz F, Lenz HJ, Leslie G, Lessel D, Lester J, Levine DA, Li L, Li CI, Lindblom A, Lindor NM, Liu G, Loupakis F, Lubiński J, Maehle L, Maier C, Mannermaa A, Marchand LL, Margolin S, May T, McGuffog L, Meindl A, Middha P, Miller A, Milne RL, MacInnis RJ, Modugno F, Montagna M, Moreno V, Moysich KB, Mucci L, Muir K, Mulligan AM, Nathanson KL, Neal DE, Ness AR, Neuhausen SL, Nevanlinna H, Newcomb PA, Newcomb LF, Nielsen FC, Nikitina-Zake L, Nordestgaard BG, Nussbaum RL, Offit K, Olah E, Olama AAA, Olopade OI, Olshan AF, Olsson H, Osorio A, Pandha H, Park JY, Pashayan N, Parsons MT, Pejovic T, Penney KL, Peters WHM, Phelan CM, Phipps AI, Plaseska-Karanfilska D, Pring M, Prokofyeva D, Radice P, Stefansson K, Ramus SJ, Raskin L, Rennert G, Rennert HS, van Rensburg EJ, Riggan MJ, Risch HA, Risch A, Roobol MJ, Rosenstein BS, Rossing MA, De Ruyck K, Saloustros E, Sandler DP, Sawyer EJ, Schabath MB, Schleutker J, Schmidt MK, Setiawan VW, Shen H, Siegel EM, Sieh W, Singer CF, Slattery ML, Sorensen KD, Southey MC, Spurdle AB, Stanford JL, Stevens VL, Stintzing S, Stone J, Sundfeldt K, Sutphen R, Swerdlow AJ, Tajara EH, Tangen CM, Tardon A, Taylor JA, Teare MD, Teixeira MR, Terry MB, Terry KL, Thibodeau SN, Thomassen M, Bjørge L, Tischkowitz M, Toland AE, Torres D, Townsend PA, Travis RC, Tung N, Tworoger SS, Ulrich CM, Usmani N, Vachon CM, Van Nieuwenhuysen E, Vega A, Aguado-Barrera ME, Wang Q, Webb PM, Weinberg CR, Weinstein S, Weissler MC, Weitzel JN, West CML, White E, Whittemore AS, Wichmann HE, Wiklund F, Winqvist R, Wolk A, Woll P, Woods M, Wu AH, Wu X, Yannoukakos D, Zheng W, Zienolddiny S, Ziogas A, Zorn KK, Lane JM, Saxena R, Thomas D, Hung RJ, Diergaarde B, McKay J, Peters U, Hsu L, García-Closas M, Eeles RA, Chenevix-Trench G, Brennan PJ, Haiman CA, Simard J, Easton DF, Gruber SB, Pharoah PDP, Price AL, Pasaniuc B, Amos CI, Kraft P, and Lindström S

Subjects
Breast Neoplasms diagnosis, Breast Neoplasms ethnology, Breast Neoplasms pathology, Case-Control Studies, Colorectal Neoplasms diagnosis, Colorectal Neoplasms ethnology, Colorectal Neoplasms pathology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Head and Neck Neoplasms diagnosis, Head and Neck Neoplasms ethnology, Head and Neck Neoplasms pathology, Humans, Lung Neoplasms diagnosis, Lung Neoplasms ethnology, Lung Neoplasms pathology, Male, Mental Disorders ethnology, Mental Disorders genetics, Mental Disorders physiopathology, Neoplasm Proteins genetics, Ovarian Neoplasms diagnosis, Ovarian Neoplasms ethnology, Ovarian Neoplasms pathology, Phenotype, Polymorphism, Single Nucleotide, Prostatic Neoplasms diagnosis, Prostatic Neoplasms ethnology, Prostatic Neoplasms pathology, Smoking ethnology, Smoking genetics, Smoking physiopathology, White People, Breast Neoplasms genetics, Colorectal Neoplasms genetics, Head and Neck Neoplasms genetics, Inheritance Patterns, Lung Neoplasms genetics, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r g  = 0.57, p = 4.6 × 10 -8 ), breast and ovarian cancer (r g  = 0.24, p = 7 × 10 -5 ), breast and lung cancer (r g  = 0.18, p =1.5 × 10 -6 ) and breast and colorectal cancer (r g  = 0.15, p = 1.1 × 10 -4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Published
2019
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13. Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece.

Author

Konstanta I, Fostira F, Apostolou P, Stratikos E, Kalfakakou D, Pampanos A, Kollia P, Papadimitriou C, Konstantopoulou I, and Yannoukakos D

Subjects
Adult, Aged, Aged, 80 and over, Breast Neoplasms drug therapy, Breast Neoplasms epidemiology, Female, Greece epidemiology, Humans, Middle Aged, Ovarian Neoplasms drug therapy, Ovarian Neoplasms epidemiology, Breast Neoplasms genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Neoplasm Proteins genetics, Ovarian Neoplasms genetics
Abstract

RAD51D gene's protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.

Published
2018
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14. A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Author

Lu Y, Beeghly-Fadiel A, Wu L, Guo X, Li B, Schildkraut JM, Im HK, Chen YA, Permuth JB, Reid BM, Teer JK, Moysich KB, Andrulis IL, Anton-Culver H, Arun BK, Bandera EV, Barkardottir RB, Barnes DR, Benitez J, Bjorge L, Brenton J, Butzow R, Caldes T, Caligo MA, Campbell I, Chang-Claude J, Claes KBM, Couch FJ, Cramer DW, Daly MB, deFazio A, Dennis J, Diez O, Domchek SM, Dörk T, Easton DF, Eccles DM, Fasching PA, Fortner RT, Fountzilas G, Friedman E, Ganz PA, Garber J, Giles GG, Godwin AK, Goldgar DE, Goodman MT, Greene MH, Gronwald J, Hamann U, Heitz F, Hildebrandt MAT, Høgdall CK, Hollestelle A, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James P, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Kwong A, Le ND, Leslie G, Lesueur F, Levine DA, Mattiello A, May T, McGuffog L, McNeish IA, Merritt MA, Modugno F, Montagna M, Neuhausen SL, Nevanlinna H, Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olson SH, Olsson H, Osorio A, Park SK, Parsons MT, Peeters PHM, Pejovic T, Peterlongo P, Phelan CM, Pujana MA, Ramus SJ, Rennert G, Risch H, Rodriguez GC, Rodríguez-Antona C, Romieu I, Rookus MA, Rossing MA, Rzepecka IK, Sandler DP, Schmutzler RK, Setiawan VW, Sharma P, Sieh W, Simard J, Singer CF, Song H, Southey MC, Spurdle AB, Sutphen R, Swerdlow AJ, Teixeira MR, Teo SH, Thomassen M, Tischkowitz M, Toland AE, Trichopoulou A, Tung N, Tworoger SS, van Rensburg EJ, Vanderstichele A, Vega A, Edwards DV, Webb PM, Weitzel JN, Wentzensen N, White E, Wolk A, Wu AH, Yannoukakos D, Zorn KK, Gayther SA, Antoniou AC, Berchuck A, Goode EL, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, and Long J

Subjects
Carcinogenesis, Cohort Studies, Female, Gene Expression Profiling, Genotype, Humans, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Risk Factors, Carcinoma, Ovarian Epithelial genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Ovarian Neoplasms genetics, Transcriptome
Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis -predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10 -6 , we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10 -7 , the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained ( P < 1.47 × 10 -3 ). These data identify one novel locus (FZD4 ) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Published
2018
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15. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author

Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chornokur G, Earp MA, Lyra PC Jr, Lee JM, Coetzee S, Beesley J, McGuffog L, Soucy P, Dicks E, Lee A, Barrowdale D, Lecarpentier J, Leslie G, Aalfs CM, Aben KKH, Adams M, Adlard J, Andrulis IL, Anton-Culver H, Antonenkova N, Aravantinos G, Arnold N, Arun BK, Arver B, Azzollini J, Balmaña J, Banerjee SN, Barjhoux L, Barkardottir RB, Bean Y, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Birrer MJ, Bjorge L, Black A, Blankstein K, Blok MJ, Bodelon C, Bogdanova N, Bojesen A, Bonanni B, Borg Å, Bradbury AR, Brenton JD, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Bruinsma F, Brunet J, Buecher B, Butzow R, Buys SS, Caldes T, Caligo MA, Campbell I, Cannioto R, Carney ME, Cescon T, Chan SB, Chang-Claude J, Chanock S, Chen XQ, Chiew YE, Chiquette J, Chung WK, Claes KBM, Conner T, Cook LS, Cook J, Cramer DW, Cunningham JM, D'Aloisio AA, Daly MB, Damiola F, Damirovna SD, Dansonka-Mieszkowska A, Dao F, Davidson R, DeFazio A, Delnatte C, Doheny KF, Diez O, Ding YC, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dossus L, Duran M, Dürst M, Dworniczak B, Eccles D, Edwards T, Eeles R, Eilber U, Ejlertsen B, Ekici AB, Ellis S, Elvira M, Eng KH, Engel C, Evans DG, Fasching PA, Ferguson S, Ferrer SF, Flanagan JM, Fogarty ZC, Fortner RT, Fostira F, Foulkes WD, Fountzilas G, Fridley BL, Friebel TM, Friedman E, Frost D, Ganz PA, Garber J, García MJ, Garcia-Barberan V, Gehrig A, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goldgar DE, Goranova T, Gore M, Greene MH, Gronwald J, Gruber S, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TVO, Harrington PA, Harris HR, Hauke J, Hein A, Henderson A, Hildebrandt MAT, Hillemanns P, Hodgson S, Høgdall CK, Høgdall E, Hogervorst FBL, Holland H, Hooning MJ, Hosking K, Huang RY, Hulick PJ, Hung J, Hunter DJ, Huntsman DG, Huzarski T, Imyanitov EN, Isaacs C, Iversen ES, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jernetz M, Jensen A, Jensen UB, John EM, Johnatty S, Jones ME, Kannisto P, Karlan BY, Karnezis A, Kast K, Kennedy CJ, Khusnutdinova E, Kiemeney LA, Kiiski JI, Kim SW, Kjaer SK, Köbel M, Kopperud RK, Kruse TA, Kupryjanczyk J, Kwong A, Laitman Y, Lambrechts D, Larrañaga N, Larson MC, Lazaro C, Le ND, Le Marchand L, Lee JW, Lele SB, Leminen A, Leroux D, Lester J, Lesueur F, Levine DA, Liang D, Liebrich C, Lilyquist J, Lipworth L, Lissowska J, Lu KH, Lubinński J, Luccarini C, Lundvall L, Mai PL, Mendoza-Fandiño G, Manoukian S, Massuger LFAG, May T, Mazoyer S, McAlpine JN, McGuire V, McLaughlin JR, McNeish I, Meijers-Heijboer H, Meindl A, Menon U, Mensenkamp AR, Merritt MA, Milne RL, Mitchell G, Modugno F, Moes-Sosnowska J, Moffitt M, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Nathanson KL, Nedergaard L, Ness RB, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Odunsi K, Olah E, Olopade OI, Olsson H, Olswold C, O'Malley DM, Ong KR, Onland-Moret NC, Orr N, Orsulic S, Osorio A, Palli D, Papi L, Park-Simon TW, Paul J, Pearce CL, Pedersen IS, Peeters PHM, Peissel B, Peixoto A, Pejovic T, Pelttari LM, Permuth JB, Peterlongo P, Pezzani L, Pfeiler G, Phillips KA, Piedmonte M, Pike MC, Piskorz AM, Poblete SR, Pocza T, Poole EM, Poppe B, Porteous ME, Prieur F, Prokofyeva D, Pugh E, Pujana MA, Pujol P, Radice P, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rhiem K, Rice P, Richardson A, Robson M, Rodriguez GC, Rodríguez-Antona C, Romm J, Rookus MA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Salvesen HB, Sandler DP, Schoemaker MJ, Senter L, Setiawan VW, Severi G, Sharma P, Shelford T, Siddiqui N, Side LE, Sieh W, Singer CF, Sobol H, Song H, Southey MC, Spurdle AB, Stadler Z, Steinemann D, Stoppa-Lyonnet D, Sucheston-Campbell LE, Sukiennicki G, Sutphen R, Sutter C, Swerdlow AJ, Szabo CI, Szafron L, Tan YY, Taylor JA, Tea MK, Teixeira MR, Teo SH, Terry KL, Thompson PJ, Thomsen LCV, Thull DL, Tihomirova L, Tinker AV, Tischkowitz M, Tognazzo S, Toland AE, Tone A, Trabert B, Travis RC, Trichopoulou A, Tung N, Tworoger SS, van Altena AM, Van Den Berg D, van der Hout AH, van der Luijt RB, Van Heetvelde M, Van Nieuwenhuysen E, van Rensburg EJ, Vanderstichele A, Varon-Mateeva R, Vega A, Edwards DV, Vergote I, Vierkant RA, Vijai J, Vratimos A, Walker L, Walsh C, Wand D, Wang-Gohrke S, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, Whittemore AS, Wijnen JT, Wilkens LR, Wolk A, Woo M, Wu X, Wu AH, Yang H, Yannoukakos D, Ziogas A, Zorn KK, Narod SA, Easton DF, Amos CI, Schildkraut JM, Ramus SJ, Ottini L, Goodman MT, Park SK, Kelemen LE, Risch HA, Thomassen M, Offit K, Simard J, Schmutzler RK, Hazelett D, Monteiro AN, Couch FJ, Berchuck A, Chenevix-Trench G, Goode EL, Sellers TA, Gayther SA, Antoniou AC, and Pharoah PDP

Subjects
Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Mutation, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Risk Factors, Telomere-Binding Proteins genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017
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16. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

Author

Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, Beesley J, Ramus SJ, Li Q, Delgado MK, Lee JM, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arun BK, Arver B, Bandera EV, Barile M, Barkardottir RB, Barrowdale D, Beckmann MW, Benitez J, Berchuck A, Bisogna M, Bjorge L, Blomqvist C, Blot W, Bogdanova N, Bojesen A, Bojesen SE, Bolla MK, Bonanni B, Børresen-Dale AL, Brauch H, Brennan P, Brenner H, Bruinsma F, Brunet J, Buhari SA, Burwinkel B, Butzow R, Buys SS, Cai Q, Caldes T, Campbell I, Canniotto R, Chang-Claude J, Chiquette J, Choi JY, Claes KB, Cook LS, Cox A, Cramer DW, Cross SS, Cybulski C, Czene K, Daly MB, Damiola F, Dansonka-Mieszkowska A, Darabi H, Dennis J, Devilee P, Diez O, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dumont M, Ehrencrona H, Ejlertsen B, Ellis S, Engel C, Lee E, Evans DG, Fasching PA, Feliubadalo L, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Foretova L, Fostira F, Foulkes WD, Fridley BL, Friedman E, Frost D, Gambino G, Ganz PA, Garber J, García-Closas M, Gentry-Maharaj A, Ghoussaini M, Giles GG, Glasspool R, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Goode EL, Goodman MT, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hallberg E, Hamann U, Hansen TV, Harrington PA, Hartman M, Hassan N, Healey S, Heitz F, Herzog J, Høgdall E, Høgdall CK, Hogervorst FB, Hollestelle A, Hopper JL, Hulick PJ, Huzarski T, Imyanitov EN, Isaacs C, Ito H, Jakubowska A, Janavicius R, Jensen A, John EM, Johnson N, Kabisch M, Kang D, Kapuscinski M, Karlan BY, Khan S, Kiemeney LA, Kjaer SK, Knight JA, Konstantopoulou I, Kosma VM, Kristensen V, Kupryjanczyk J, Kwong A, de la Hoya M, Laitman Y, Lambrechts D, Le N, De Leeneer K, Lester J, Levine DA, Li J, Lindblom A, Long J, Lophatananon A, Loud JT, Lu K, Lubinski J, Mannermaa A, Manoukian S, Le Marchand L, Margolin S, Marme F, Massuger LF, Matsuo K, Mazoyer S, McGuffog L, McLean C, McNeish I, Meindl A, Menon U, Mensenkamp AR, Milne RL, Montagna M, Moysich KB, Muir K, Mulligan AM, Nathanson KL, Ness RB, Neuhausen SL, Nevanlinna H, Nord S, Nussbaum RL, Odunsi K, Offit K, Olah E, Olopade OI, Olson JE, Olswold C, O'Malley D, Orlow I, Orr N, Osorio A, Park SK, Pearce CL, Pejovic T, Peterlongo P, Pfeiler G, Phelan CM, Poole EM, Pylkäs K, Radice P, Rantala J, Rashid MU, Rennert G, Rhenius V, Rhiem K, Risch HA, Rodriguez G, Rossing MA, Rudolph A, Salvesen HB, Sangrajrang S, Sawyer EJ, Schildkraut JM, Schmidt MK, Schmutzler RK, Sellers TA, Seynaeve C, Shah M, Shen CY, Shu XO, Sieh W, Singer CF, Sinilnikova OM, Slager S, Song H, Soucy P, Southey MC, Stenmark-Askmalm M, Stoppa-Lyonnet D, Sutter C, Swerdlow A, Tchatchou S, Teixeira MR, Teo SH, Terry KL, Terry MB, Thomassen M, Tibiletti MG, Tihomirova L, Tognazzo S, Toland AE, Tomlinson I, Torres D, Truong T, Tseng CC, Tung N, Tworoger SS, Vachon C, van den Ouweland AM, van Doorn HC, van Rensburg EJ, Van't Veer LJ, Vanderstichele A, Vergote I, Vijai J, Wang Q, Wang-Gohrke S, Weitzel JN, Wentzensen N, Whittemore AS, Wildiers H, Winqvist R, Wu AH, Yannoukakos D, Yoon SY, Yu JC, Zheng W, Zheng Y, Khanna KK, Simard J, Monteiro AN, French JD, Couch FJ, Freedman ML, Easton DF, Dunning AM, Pharoah PD, Edwards SL, Chenevix-Trench G, Antoniou AC, and Gayther SA

Subjects
Asian People genetics, Black People genetics, Female, Genome-Wide Association Study, Genotype, Humans, RNA, Messenger genetics, RNA, Messenger metabolism, Alleles, Breast Neoplasms genetics, Chromosomes, Human, Pair 19 genetics, Genetic Predisposition to Disease, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

Published
2016
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17. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

Author

Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, Lawrenson K, Lindstrom S, Ramus SJ, Thompson DJ, Kibel AS, Dansonka-Mieszkowska A, Michael A, Dieffenbach AK, Gentry-Maharaj A, Whittemore AS, Wolk A, Monteiro A, Peixoto A, Kierzek A, Cox A, Rudolph A, Gonzalez-Neira A, Wu AH, Lindblom A, Swerdlow A, Ziogas A, Ekici AB, Burwinkel B, Karlan BY, Nordestgaard BG, Blomqvist C, Phelan C, McLean C, Pearce CL, Vachon C, Cybulski C, Slavov C, Stegmaier C, Maier C, Ambrosone CB, Høgdall CK, Teerlink CC, Kang D, Tessier DC, Schaid DJ, Stram DO, Cramer DW, Neal DE, Eccles D, Flesch-Janys D, Edwards DR, Wokozorczyk D, Levine DA, Yannoukakos D, Sawyer EJ, Bandera EV, Poole EM, Goode EL, Khusnutdinova E, Høgdall E, Song F, Bruinsma F, Heitz F, Modugno F, Hamdy FC, Wiklund F, Giles GG, Olsson H, Wildiers H, Ulmer HU, Pandha H, Risch HA, Darabi H, Salvesen HB, Nevanlinna H, Gronberg H, Brenner H, Brauch H, Anton-Culver H, Song H, Lim HY, McNeish I, Campbell I, Vergote I, Gronwald J, Lubiński J, Stanford JL, Benítez J, Doherty JA, Permuth JB, Chang-Claude J, Donovan JL, Dennis J, Schildkraut JM, Schleutker J, Hopper JL, Kupryjanczyk J, Park JY, Figueroa J, Clements JA, Knight JA, Peto J, Cunningham JM, Pow-Sang J, Batra J, Czene K, Lu KH, Herkommer K, Khaw KT, Matsuo K, Muir K, Offitt K, Chen K, Moysich KB, Aittomäki K, Odunsi K, Kiemeney LA, Massuger LF, Fitzgerald LM, Cook LS, Cannon-Albright L, Hooning MJ, Pike MC, Bolla MK, Luedeke M, Teixeira MR, Goodman MT, Schmidt MK, Riggan M, Aly M, Rossing MA, Beckmann MW, Moisse M, Sanderson M, Southey MC, Jones M, Lush M, Hildebrandt MA, Hou MF, Schoemaker MJ, Garcia-Closas M, Bogdanova N, Rahman N, Le ND, Orr N, Wentzensen N, Pashayan N, Peterlongo P, Guénel P, Brennan P, Paulo P, Webb PM, Broberg P, Fasching PA, Devilee P, Wang Q, Cai Q, Li Q, Kaneva R, Butzow R, Kopperud RK, Schmutzler RK, Stephenson RA, MacInnis RJ, Hoover RN, Winqvist R, Ness R, Milne RL, Travis RC, Benlloch S, Olson SH, McDonnell SK, Tworoger SS, Maia S, Berndt S, Lee SC, Teo SH, Thibodeau SN, Bojesen SE, Gapstur SM, Kjær SK, Pejovic T, Tammela TL, Dörk T, Brüning T, Wahlfors T, Key TJ, Edwards TL, Menon U, Hamann U, Mitev V, Kosma VM, Setiawan VW, Kristensen V, Arndt V, Vogel W, Zheng W, Sieh W, Blot WJ, Kluzniak W, Shu XO, Gao YT, Schumacher F, Freedman ML, Berchuck A, Dunning AM, Simard J, Haiman CA, Spurdle A, Sellers TA, Hunter DJ, Henderson BE, Kraft P, Chanock SJ, Couch FJ, Hall P, Gayther SA, Easton DF, Chenevix-Trench G, Eeles R, Pharoah PD, and Lambrechts D

Subjects
Breast Neoplasms metabolism, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Humans, Male, Meta-Analysis as Topic, Organ Specificity genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms metabolism, Quantitative Trait Loci, Signal Transduction, Breast Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
Abstract

Unlabelled: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Published
2016
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18. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Author

Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, Mazoyer S, Chenevix-Trench G, Easton DF, Antoniou AC, Nathanson KL, Laitman Y, Kushnir A, Paluch-Shimon S, Berger R, Zidan J, Friedman E, Ehrencrona H, Stenmark-Askmalm M, Einbeigi Z, Loman N, Harbst K, Rantala J, Melin B, Huo D, Olopade OI, Seldon J, Ganz PA, Nussbaum RL, Chan SB, Odunsi K, Gayther SA, Domchek SM, Arun BK, Lu KH, Mitchell G, Karlan BY, Walsh C, Lester J, Godwin AK, Pathak H, Ross E, Daly MB, Whittemore AS, John EM, Miron A, Terry MB, Chung WK, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Ejlertsen B, Gerdes AM, Hansen Tv, Ramón y Cajal T, Osorio A, Benitez J, Godino J, Tejada MI, Duran M, Weitzel JN, Bobolis KA, Sand SR, Fontaine A, Savarese A, Pasini B, Peissel B, Bonanni B, Zaffaroni D, Vignolo-Lutati F, Scuvera G, Giannini G, Bernard L, Genuardi M, Radice P, Dolcetti R, Manoukian S, Pensotti V, Gismondi V, Yannoukakos D, Fostira F, Garber J, Torres D, Rashid MU, Hamann U, Peock S, Frost D, Platte R, Evans DG, Eeles R, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Hodgson S, Morrison PJ, Walker L, Porteous ME, Kennedy MJ, Izatt L, Adlard J, Donaldson A, Ellis S, Sharma P, Schmutzler RK, Wappenschmidt B, Becker A, Rhiem K, Hahnen E, Engel C, Meindl A, Engert S, Ditsch N, Arnold N, Plendl HJ, Mundhenke C, Niederacher D, Fleisch M, Sutter C, Bartram CR, Dikow N, Wang-Gohrke S, Gadzicki D, Steinemann D, Kast K, Beer M, Varon-Mateeva R, Gehrig A, Weber BH, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Houdayer C, Belotti M, Gauthier-Villars M, Damiola F, Boutry-Kryza N, Lasset C, Sobol H, Peyrat JP, Muller D, Fricker JP, Collonge-Rame MA, Mortemousque I, Nogues C, Rouleau E, Isaacs C, De Paepe A, Poppe B, Claes K, De Leeneer K, Piedmonte M, Rodriguez G, Wakely K, Boggess J, Blank SV, Basil J, Azodi M, Phillips KA, Caldes T, de la Hoya M, Romero A, Nevanlinna H, Aittomäki K, van der Hout AH, Hogervorst FB, Verhoef S, Collée JM, Seynaeve C, Oosterwijk JC, Gille JJ, Wijnen JT, Gómez Garcia EB, Kets CM, Ausems MG, Aalfs CM, Devilee P, Mensenkamp AR, Kwong A, Olah E, Papp J, Diez O, Lazaro C, Darder E, Blanco I, Salinas M, Jakubowska A, Lubinski J, Gronwald J, Jaworska-Bieniek K, Durda K, Sukiennicki G, Huzarski T, Byrski T, Cybulski C, Toloczko-Grabarek A, Złowocka-Perłowska E, Menkiszak J, Arason A, Barkardottir RB, Simard J, Laframboise R, Montagna M, Agata S, Alducci E, Peixoto A, Teixeira MR, Spurdle AB, Lee MH, Park SK, Kim SW, Friebel TM, Couch FJ, Lindor NM, Pankratz VS, Guidugli L, Wang X, Tischkowitz M, Foretova L, Vijai J, Offit K, Robson M, Rau-Murthy R, Kauff N, Fink-Retter A, Singer CF, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Berger A, Greene MH, Mai PL, Imyanitov EN, Toland AE, Senter L, Bojesen A, Pedersen IS, Skytte AB, Sunde L, Thomassen M, Moeller ST, Kruse TA, Jensen UB, Caligo MA, Aretini P, Teo SH, Selkirk CG, Hulick PJ, and Andrulis I

Subjects
Adult, Age of Onset, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Mutation, Ovarian Neoplasms genetics
Abstract

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists., Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2., Design, Setting, and Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk., Exposures: Mutations of BRCA1 or BRCA2., Main Outcomes and Measures: Breast and ovarian cancer risks., Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers., Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Published
2015
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19. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Osorio A, Milne RL, Kuchenbaecker K, Vaclová T, Pita G, Alonso R, Peterlongo P, Blanco I, de la Hoya M, Duran M, Díez O, Ramón Y Cajal T, Konstantopoulou I, Martínez-Bouzas C, Andrés Conejero R, Soucy P, McGuffog L, Barrowdale D, Lee A, Arver B, Rantala J, Loman N, Ehrencrona H, Olopade OI, Beattie MS, Domchek SM, Nathanson K, Rebbeck TR, Arun BK, Karlan BY, Walsh C, Lester J, John EM, Whittemore AS, Daly MB, Southey M, Hopper J, Terry MB, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Hansen TV, Jønson L, Ejlertsen B, Gerdes AM, Infante M, Herráez B, Moreno LT, Weitzel JN, Herzog J, Weeman K, Manoukian S, Peissel B, Zaffaroni D, Scuvera G, Bonanni B, Mariette F, Volorio S, Viel A, Varesco L, Papi L, Ottini L, Tibiletti MG, Radice P, Yannoukakos D, Garber J, Ellis S, Frost D, Platte R, Fineberg E, Evans G, Lalloo F, Izatt L, Eeles R, Adlard J, Davidson R, Cole T, Eccles D, Cook J, Hodgson S, Brewer C, Tischkowitz M, Douglas F, Porteous M, Side L, Walker L, Morrison P, Donaldson A, Kennedy J, Foo C, Godwin AK, Schmutzler RK, Wappenschmidt B, Rhiem K, Engel C, Meindl A, Ditsch N, Arnold N, Plendl HJ, Niederacher D, Sutter C, Wang-Gohrke S, Steinemann D, Preisler-Adams S, Kast K, Varon-Mateeva R, Gehrig A, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Damiola F, Poppe B, Claes K, Piedmonte M, Tucker K, Backes F, Rodríguez G, Brewster W, Wakeley K, Rutherford T, Caldés T, Nevanlinna H, Aittomäki K, Rookus MA, van Os TA, van der Kolk L, de Lange JL, Meijers-Heijboer HE, van der Hout AH, van Asperen CJ, Gómez Garcia EB, Hoogerbrugge N, Collée JM, van Deurzen CH, van der Luijt RB, Devilee P, Olah E, Lázaro C, Teulé A, Menéndez M, Jakubowska A, Cybulski C, Gronwald J, Lubinski J, Durda K, Jaworska-Bieniek K, Johannsson OT, Maugard C, Montagna M, Tognazzo S, Teixeira MR, Healey S, Olswold C, Guidugli L, Lindor N, Slager S, Szabo CI, Vijai J, Robson M, Kauff N, Zhang L, Rau-Murthy R, Fink-Retter A, Singer CF, Rappaport C, Geschwantler Kaulich D, Pfeiler G, Tea MK, Berger A, Phelan CM, Greene MH, Mai PL, Lejbkowicz F, Andrulis I, Mulligan AM, Glendon G, Toland AE, Bojesen A, Pedersen IS, Sunde L, Thomassen M, Kruse TA, Jensen UB, Friedman E, Laitman Y, Shimon SP, Simard J, Easton DF, Offit K, Couch FJ, Chenevix-Trench G, Antoniou AC, and Benitez J

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Female, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Risk, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, DNA Glycosylases genetics, DNA Repair genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide genetics
Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Published
2014
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20. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Author

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, Lawrenson K, Stutz MD, Lu Y, Karevan R, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, Rossing MA, Pita G, Doherty JA, Alvarez N, Larson MC, Fridley BL, Schoof N, Chang-Claude J, Cicek MS, Peto J, Kalli KR, Broeks A, Armasu SM, Schmidt MK, Braaf LM, Winterhoff B, Nevanlinna H, Konecny GE, Lambrechts D, Rogmann L, Guénel P, Teoman A, Milne RL, Garcia JJ, Cox A, Shridhar V, Burwinkel B, Marme F, Hein R, Sawyer EJ, Haiman CA, Wang-Gohrke S, Andrulis IL, Moysich KB, Hopper JL, Odunsi K, Lindblom A, Giles GG, Brenner H, Simard J, Lurie G, Fasching PA, Carney ME, Radice P, Wilkens LR, Swerdlow A, Goodman MT, Brauch H, Garcia-Closas M, Hillemanns P, Winqvist R, Dürst M, Devilee P, Runnebaum I, Jakubowska A, Lubinski J, Mannermaa A, Butzow R, Bogdanova NV, Dörk T, Pelttari LM, Zheng W, Leminen A, Anton-Culver H, Bunker CH, Kristensen V, Ness RB, Muir K, Edwards R, Meindl A, Heitz F, Matsuo K, du Bois A, Wu AH, Harter P, Teo SH, Schwaab I, Shu XO, Blot W, Hosono S, Kang D, Nakanishi T, Hartman M, Yatabe Y, Hamann U, Karlan BY, Sangrajrang S, Kjaer SK, Gaborieau V, Jensen A, Eccles D, Høgdall E, Shen CY, Brown J, Woo YL, Shah M, Azmi MA, Luben R, Omar SZ, Czene K, Vierkant RA, Nordestgaard BG, Flyger H, Vachon C, Olson JE, Wang X, Levine DA, Rudolph A, Weber RP, Flesch-Janys D, Iversen E, Nickels S, Schildkraut JM, Silva Idos S, Cramer DW, Gibson L, Terry KL, Fletcher O, Vitonis AF, van der Schoot CE, Poole EM, Hogervorst FB, Tworoger SS, Liu J, Bandera EV, Li J, Olson SH, Humphreys K, Orlow I, Blomqvist C, Rodriguez-Rodriguez L, Aittomäki K, Salvesen HB, Muranen TA, Wik E, Brouwers B, Krakstad C, Wauters E, Halle MK, Wildiers H, Kiemeney LA, Mulot C, Aben KK, Laurent-Puig P, Altena AM, Truong T, Massuger LF, Benitez J, Pejovic T, Perez JI, Hoatlin M, Zamora MP, Cook LS, Balasubramanian SP, Kelemen LE, Schneeweiss A, Le ND, Sohn C, Brooks-Wilson A, Tomlinson I, Kerin MJ, Miller N, Cybulski C, Henderson BE, Menkiszak J, Schumacher F, Wentzensen N, Le Marchand L, Yang HP, Mulligan AM, Glendon G, Engelholm SA, Knight JA, Høgdall CK, Apicella C, Gore M, Tsimiklis H, Song H, Southey MC, Jager A, den Ouweland AM, Brown R, Martens JW, Flanagan JM, Kriege M, Paul J, Margolin S, Siddiqui N, Severi G, Whittemore AS, Baglietto L, McGuire V, Stegmaier C, Sieh W, Müller H, Arndt V, Labrèche F, Gao YT, Goldberg MS, Yang G, Dumont M, McLaughlin JR, Hartmann A, Ekici AB, Beckmann MW, Phelan CM, Lux MP, Permuth-Wey J, Peissel B, Sellers TA, Ficarazzi F, Barile M, Ziogas A, Ashworth A, Gentry-Maharaj A, Jones M, Ramus SJ, Orr N, Menon U, Pearce CL, Brüning T, Pike MC, Ko YD, Lissowska J, Figueroa J, Kupryjanczyk J, Chanock SJ, Dansonka-Mieszkowska A, Jukkola-Vuorinen A, Rzepecka IK, Pylkäs K, Bidzinski M, Kauppila S, Hollestelle A, Seynaeve C, Tollenaar RA, Durda K, Jaworska K, Hartikainen JM, Kosma VM, Kataja V, Antonenkova NN, Long J, Shrubsole M, Deming-Halverson S, Lophatananon A, Siriwanarangsan P, Stewart-Brown S, Ditsch N, Lichtner P, Schmutzler RK, Ito H, Iwata H, Tajima K, Tseng CC, Stram DO, van den Berg D, Yip CH, Ikram MK, Teh YC, Cai H, Lu W, Signorello LB, Cai Q, Noh DY, Yoo KY, Miao H, Iau PT, Teo YY, McKay J, Shapiro C, Ademuyiwa F, Fountzilas G, Hsiung CN, Yu JC, Hou MF, Healey CS, Luccarini C, Peock S, Stoppa-Lyonnet D, Peterlongo P, Rebbeck TR, Piedmonte M, Singer CF, Friedman E, Thomassen M, Offit K, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Garber J, Narod SA, Weitzel JN, Montagna M, Olah E, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Imyanitov EN, Tihomirova L, Arun BK, Campbell I, Mensenkamp AR, van Asperen CJ, van Roozendaal KE, Meijers-Heijboer H, Collée JM, Oosterwijk JC, Hooning MJ, Rookus MA, van der Luijt RB, Os TA, Evans DG, Frost D, Fineberg E, Barwell J, Walker L, Kennedy MJ, Platte R, Davidson R, Ellis SD, Cole T, Bressac-de Paillerets B, Buecher B, Damiola F, Faivre L, Frenay M, Sinilnikova OM, Caron O, Giraud S, Mazoyer S, Bonadona V, Caux-Moncoutier V, Toloczko-Grabarek A, Gronwald J, Byrski T, Spurdle AB, Bonanni B, Zaffaroni D, Giannini G, Bernard L, Dolcetti R, Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea MK, Paluch SS, Laitman Y, Skytte AB, Kruse TA, Jensen UB, Robson M, Gerdes AM, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro AN, Gayther SA, Pharoah PD, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, and Dunning AM

Subjects
Alternative Splicing, Breast Neoplasms pathology, Case-Control Studies, Chromatin genetics, DNA Methylation, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases metabolism, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms etiology, Genetic Loci genetics, Ovarian Neoplasms etiology, Polymorphism, Single Nucleotide genetics, Telomerase genetics, Telomere genetics
Abstract

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Published
2013
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21. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

Author

Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, Soucy P, Fredericksen Z, Barrowdale D, Dennis J, Gaudet MM, Dicks E, Kosel M, Healey S, Sinilnikova OM, Lee A, Bacot F, Vincent D, Hogervorst FB, Peock S, Stoppa-Lyonnet D, Jakubowska A, Radice P, Schmutzler RK, Domchek SM, Piedmonte M, Singer CF, Friedman E, Thomassen M, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Greene MH, Karlan BY, Garber J, Phelan CM, Weitzel JN, Montagna M, Olah E, Andrulis IL, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Nevanlinna H, Osorio A, Terry MB, Daly MB, van Rensburg EJ, Hamann U, Ramus SJ, Toland AE, Caligo MA, Olopade OI, Tung N, Claes K, Beattie MS, Southey MC, Imyanitov EN, Tischkowitz M, Janavicius R, John EM, Kwong A, Diez O, Balmaña J, Barkardottir RB, Arun BK, Rennert G, Teo SH, Ganz PA, Campbell I, van der Hout AH, van Deurzen CH, Seynaeve C, Gómez Garcia EB, van Leeuwen FE, Meijers-Heijboer HE, Gille JJ, Ausems MG, Blok MJ, Ligtenberg MJ, Rookus MA, Devilee P, Verhoef S, van Os TA, Wijnen JT, Frost D, Ellis S, Fineberg E, Platte R, Evans DG, Izatt L, Eeles RA, Adlard J, Eccles DM, Cook J, Brewer C, Douglas F, Hodgson S, Morrison PJ, Side LE, Donaldson A, Houghton C, Rogers MT, Dorkins H, Eason J, Gregory H, McCann E, Murray A, Calender A, Hardouin A, Berthet P, Delnatte C, Nogues C, Lasset C, Houdayer C, Leroux D, Rouleau E, Prieur F, Damiola F, Sobol H, Coupier I, Venat-Bouvet L, Castera L, Gauthier-Villars M, Léoné M, Pujol P, Mazoyer S, Bignon YJ, Złowocka-Perłowska E, Gronwald J, Lubinski J, Durda K, Jaworska K, Huzarski T, Spurdle AB, Viel A, Peissel B, Bonanni B, Melloni G, Ottini L, Papi L, Varesco L, Tibiletti MG, Peterlongo P, Volorio S, Manoukian S, Pensotti V, Arnold N, Engel C, Deissler H, Gadzicki D, Gehrig A, Kast K, Rhiem K, Meindl A, Niederacher D, Ditsch N, Plendl H, Preisler-Adams S, Engert S, Sutter C, Varon-Mateeva R, Wappenschmidt B, Weber BH, Arver B, Stenmark-Askmalm M, Loman N, Rosenquist R, Einbeigi Z, Nathanson KL, Rebbeck TR, Blank SV, Cohn DE, Rodriguez GC, Small L, Friedlander M, Bae-Jump VL, Fink-Retter A, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Lindor NM, Kaufman B, Shimon Paluch S, Laitman Y, Skytte AB, Gerdes AM, Pedersen IS, Moeller ST, Kruse TA, Jensen UB, Vijai J, Sarrel K, Robson M, Kauff N, Mulligan AM, Glendon G, Ozcelik H, Ejlertsen B, Nielsen FC, Jønson L, Andersen MK, Ding YC, Steele L, Foretova L, Teulé A, Lazaro C, Brunet J, Pujana MA, Mai PL, Loud JT, Walsh C, Lester J, Orsulic S, Narod SA, Herzog J, Sand SR, Tognazzo S, Agata S, Vaszko T, Weaver J, Stavropoulou AV, Buys SS, Romero A, de la Hoya M, Aittomäki K, Muranen TA, Duran M, Chung WK, Lasa A, Dorfling CM, Miron A, Benitez J, Senter L, Huo D, Chan SB, Sokolenko AP, Chiquette J, Tihomirova L, Friebel TM, Agnarsson BA, Lu KH, Lejbkowicz F, James PA, Hall P, Dunning AM, Tessier D, Cunningham J, Slager SL, Wang C, Hart S, Stevens K, Simard J, Pastinen T, Pankratz VS, Offit K, Easton DF, Chenevix-Trench G, and Antoniou AC

Subjects
BRCA2 Protein genetics, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, BRCA1 Protein genetics, Breast Neoplasms genetics, Genome-Wide Association Study, Ovarian Neoplasms genetics
Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Competing Interests: The authors have declared that no competing interests exist.

Published
2013
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22. Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.

Author

Stavropoulou AV, Fostira F, Pertesi M, Tsitlaidou M, Voutsinas GE, Triantafyllidou O, Bamias A, Dimopoulos MA, Timotheadou E, Pectasides D, Christodoulou C, Klouvas G, Papadimitriou C, Makatsoris T, Pentheroudakis G, Aravantinos G, Karydakis V, Yannoukakos D, Fountzilas G, and Konstantopoulou I

Subjects
Adolescent, Adult, Age Factors, Age of Onset, Aged, Aged, 80 and over, Child, Exons, Family, Female, Genes, BRCA2, Greece epidemiology, Heterozygote, Humans, Middle Aged, Ovarian Neoplasms pathology, Pedigree, Phenotype, Prevalence, Young Adult, Genes, BRCA1, Mutation, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
Abstract

Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.

Published
2013
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23. International distribution and age estimation of the Portuguese BRCA2 c.156&#95;157insAlu founder mutation.

Author

Peixoto A, Santos C, Pinheiro M, Pinto P, Soares MJ, Rocha P, Gusmão L, Amorim A, van der Hout A, Gerdes AM, Thomassen M, Kruse TA, Cruger D, Sunde L, Bignon YJ, Uhrhammer N, Cornil L, Rouleau E, Lidereau R, Yannoukakos D, Pertesi M, Narod S, Royer R, Costa MM, Lazaro C, Feliubadaló L, Graña B, Blanco I, de la Hoya M, Caldés T, Maillet P, Benais-Pont G, Pardo B, Laitman Y, Friedman E, Velasco EA, Durán M, Miramar MD, Valle AR, Calvo MT, Vega A, Blanco A, Diez O, Gutiérrez-Enríquez S, Balmaña J, Ramon y Cajal T, Alonso C, Baiget M, Foulkes W, Tischkowitz M, Kyle R, Sabbaghian N, Ashton-Prolla P, Ewald IP, Rajkumar T, Mota-Vieira L, Giannini G, Gulino A, Achatz MI, Carraro DM, de Paillerets BB, Remenieras A, Benson C, Casadei S, King MC, Teugels E, and Teixeira MR

Subjects
Amino Acid Sequence, Female, Founder Effect, Genetic Predisposition to Disease, Genetic Testing, Genetics, Population, Humans, Microsatellite Repeats, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Portugal epidemiology, RNA, Messenger analysis, Reading Frames genetics, Sequence Deletion, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genes, BRCA2, Mutation, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
Abstract

The c.156&#95;157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156&#95;157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156&#95;157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.

Published
2011
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24. G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history.

Author

Anagnostopoulos T, Pertesi M, Konstantopoulou I, Armaou S, Kamakari S, Nasioulas G, Athanasiou A, Dobrovic A, Young MA, Goldgar D, Fountzilas G, and Yannoukakos D

Subjects
Adult, Age of Onset, Family Health, Female, Genetic Predisposition to Disease, Genetic Testing, Humans, Likelihood Functions, Microsatellite Repeats, Middle Aged, BRCA1 Protein genetics, Breast Neoplasms ethnology, Breast Neoplasms genetics, Genes, BRCA1, Mutation, Ovarian Neoplasms ethnology, Ovarian Neoplasms genetics
Abstract

We have performed screening in 287 breast/ovarian cancer families in Greece which has revealed that approximately 12% (8/65) of all index patients-carriers of a deleterious mutation in BRCA1 and BRCA2 genes, contain the base substitution G to A at position 5331 of BRCA1 gene. This generates the amino acid change G1738R for which based on a combination of genetic, in silico and histopathological analysis there are strong suggestions that it is a causative mutation. In this paper, we present further evidence suggesting the pathogenicity of this variant. Forty breast/ovarian cancer patients were reported in 11 Greek families: the above eight living in Greece, two living in Australia and one in USA, all containing G1738R. Twenty of these patients were screened and were all found to be carriers of the same base substitution. In addition, we have detected the same base change in five breast/ovarian cancer patients after screening 475 unselected patient samples with no apparent family history. The mean age of onset for all the above patients was 39.4 and 53.6 years for breast and ovarian cancer cases, respectively. A multi-factorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 developed previously was applied on G1738R and the odds of it being a deleterious mutation was estimated to be 11470:1. In order to explain the prevalence of this mutation mainly in the Greek population, its genealogical history was examined. DNA samples were collected from 11 carrier families living in Greece, Australia and USA. Screening of eight intragenic SNPs, three intragenic and seven extragenic microsatellite markers and comparison with control individuals, suggested a common origin for the mutation while the time to its most recent common ancestor was estimated to be 11 generations (about 275 years assuming a generational interval of 25 years) with a 1-lod support interval of 4-24 generations (100-600 years). Considering the large degree of genetic heterogeneity in the Greek population, the identification of a frequent founder mutation greatly facilitates genetic screening.

Published
2008
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25. Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients.

Author

Konstantopoulou I, Rampias T, Ladopoulou A, Koutsodontis G, Armaou S, Anagnostopoulos T, Nikolopoulos G, Kamakari S, Nounesis G, Stylianakis A, Karanikiotis C, Razis E, Gogas H, Keramopoulos A, Gaki V, Markopoulos C, Skarlos D, Pandis N, Bei T, Arzimanoglou I, Fountzilas G, and Yannoukakos D

Subjects
Cost-Benefit Analysis, Female, Greece, Humans, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Mutation, Ovarian Neoplasms genetics
Abstract

127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level.

Published
2008
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26. Novel genomic rearrangements in the BRCA1 gene detected in Greek breast/ovarian cancer patients.

Author

Armaou S, Konstantopoulou I, Anagnostopoulos T, Razis E, Boukovinas I, Xenidis N, Fountzilas G, and Yannoukakos D

Subjects
Adult, DNA, Neoplasm analysis, Exons genetics, Female, Gene Rearrangement, Genome, Human, Greece, Humans, Pedigree, Point Mutation genetics, Polymerase Chain Reaction methods, RNA, Neoplasm, Breast Neoplasms genetics, Genes, BRCA1, Ovarian Neoplasms genetics
Abstract

The identification of genomic rearrangements in breast/ovarian cancer families has widened the mutational spectrum of the BRCA1 gene, increasing the number of patients who can benefit from molecular screening. More than 60 different BRCA1 genomic rearrangements with mapped breakpoints have been reported up to date, in all exons of the gene. The proportion of BRCA1 mutations due to genomic rearrangements varies from 8 to 27% in different populations, probably due to both ethnic diversity and the technical approach employed. In order to estimate the contribution of BRCA1 genomic rearrangements to hereditary breast/ovarian cancer (HBOC) predisposition in Greek families, probands from 95 families with breast/ovarian history but negative for point mutations or small insertions/deletions in BRCA1 and BRCA2 genes, were screened using Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF). Two large deletions of 4.2 and 4.4 kb were identified in exons 20 and 24 respectively. Additional screening, using diagnostic primers for the above deletions in exons 20 and 24, performed on another 86 probands from families with breast/ovarian cancer history and 210 cases of sporadic breast/ovarian cancer resulted in the identification of two more large genomic rearrangements. One, identified in a familial case, identical to the previous exon 24 deletion and a second, identified in a case reported as sporadic, 3.2 kb deletion involving exon 20 and reported elsewhere in another Greek patient. Three out of four genomic rearrangements described in this study were detected in patients who had developed both breast and ovarian cancer; thus suggesting a correlation between the specific phenotype and the high probability of detecting inherited rearrangements in BRCA1.

Published
2007
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27. Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers.

Author

Hughes DJ, Ginolhac SM, Coupier I, Corbex M, Bressac-de-Paillerets B, Chompret A, Bignon YJ, Uhrhammer N, Lasset C, Giraud S, Hardouin A, Berthet P, Peyrat JP, Fournier J, Nogues C, Lidereau R, Muller D, Fricker JP, Longy M, Toulas C, Guimbaud R, Maugard C, Olschwang S, Yannoukakos D, Durocher F, Moisan AM, Simard J, Mazoyer S, Lynch HT, Szabo C, Lenoir GM, Goldgar DE, Stoppa-Lyonnet D, and Sinilnikova OM

Subjects
Adult, Aged, Carrier State, Female, Gene Frequency, Genes, BRCA1, Genotype, Humans, Middle Aged, Polymorphism, Genetic, Risk, Breast Neoplasms genetics, Genes, BRCA2, Germ-Line Mutation, Ovarian Neoplasms genetics
Abstract

The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.

Published
2005

28. BRCA1 wild-type allele modifies risk of ovarian cancer in carriers of BRCA1 germ-line mutations.

Author

Ginolhac SM, Gad S, Corbex M, Bressac-De-Paillerets B, Chompret A, Bignon YJ, Peyrat JP, Fournier J, Lasset C, Giraud S, Muller D, Fricker JP, Hardouin A, Berthet P, Maugard C, Nogues C, Lidereau R, Longy M, Olschwang S, Toulas C, Guimbaud R, Yannoukakos D, Szabo C, Durocher F, Moisan AM, Simard J, Mazoyer S, Lynch HT, Goldgar D, Stoppa-Lyonnet D, Lenoir GM, and Sinilnikova OM

Subjects
Adult, Age Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Canada epidemiology, Female, Follow-Up Studies, France epidemiology, Gene Frequency genetics, Genetic Markers genetics, Greece epidemiology, Humans, Linkage Disequilibrium, Middle Aged, Ovarian Neoplasms epidemiology, Parity genetics, Polymorphism, Genetic genetics, Risk Factors, United States epidemiology, Women's Health, Alleles, Genes, BRCA1 physiology, Germ-Line Mutation genetics, Heterozygote, Ovarian Neoplasms genetics
Abstract

Strong inter- and intrafamilial variation of penetrance of breast and ovarian cancer is observed in BRCA1 mutation carriers. The wild-type copy of the BRCA1 gene is a plausible candidate as a cancer risk modifier given that the residual function corresponding to the intact BRCA1 allele may influence the process of tumor formation in BRCA1 carriers. Indeed, growing evidence is now becoming available on impaired reparation of double-strand DNA breaks in cells heterozygous for BRCA1 mutations, implying an enhanced mutability of BRCA1(+/-) cells. To determine whether certain variant forms of the wild-type BRCA1 allele are implicated in variation of the BRCA1-related cancer risk, their effect was studied in a panel of 591 women with BRCA1 germ-line mutations. We found that BRCA1 carriers with the wild-type BRCA1 copy bearing a common Gly1038 variant were at increased risk of ovarian cancer (hazards ratio, 1.50; 95% confidence interval, 1.03-2.19). The results of our study imply that a quite significant proportion of the interindividual variability in ovarian cancer penetrance in BRCA1 carriers may be explained by a common BRCA1 Gly1038 wild-type allele, given its high frequency (0.27).

Published
2003

29. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Author

O’Mahony, Denise G, Ramus, Susan J, Southey, Melissa C, Meagher, Nicola S, Hadjisavvas, Andreas, John, Esther M, Hamann, Ute, Imyanitov, Evgeny N, Andrulis, Irene L, Sharma, Priyanka, Daly, Mary B, Hake, Christopher R, Weitzel, Jeffrey N, Jakubowska, Anna, Godwin, Andrew K, Arason, Adalgeir, Bane, Anita, Simard, Jacques, Soucy, Penny, Caligo, Maria A, Mai, Phuong L, Claes, Kathleen BM, Teixeira, Manuel R, Chung, Wendy K, Lazaro, Conxi, Hulick, Peter J, Toland, Amanda E, Pedersen, Inge Sokilde, Neuhausen, Susan L, Vega, Ana, de la Hoya, Miguel, Nevanlinna, Heli, Dhawan, Mallika, Zampiga, Valentina, Danesi, Rita, Varesco, Liliana, Gismondi, Viviana, Vellone, Valerio Gaetano, James, Paul A, Janavicius, Ramunas, Nikitina-Zake, Liene, Nielsen, Finn Cilius, van Overeem Hansen, Thomas, Pejovic, Tanja, Borg, Ake, Rantala, Johanna, Offit, Kenneth, Montagna, Marco, Nathanson, Katherine L, Domchek, Susan M, Osorio, Ana, García, María J, Karlan, Beth Y, De Fazio, Anna, Bowtell, David, McGuffog, Lesley, Leslie, Goska, Parsons, Michael T, Dörk, Thilo, Speith, Lisa-Marie, dos Santos, Elizabeth Santana, da Costa, Alexandre André BA, Radice, Paolo, Peterlongo, Paolo, Papi, Laura, Engel, Christoph, Hahnen, Eric, Schmutzler, Rita K, Wappenschmidt, Barbara, Easton, Douglas F, Tischkowitz, Marc, Singer, Christian F, Tan, Yen Yen, Whittemore, Alice S, Sieh, Weiva, Brenton, James D, Yannoukakos, Drakoulis, Fostira, Florentia, Konstantopoulou, Irene, Soukupova, Jana, Vocka, Michal, Chenevix-Trench, Georgia, Pharoah, Paul DP, Antoniou, Antonis C, Goldgar, David E, Spurdle, Amanda B, and Michailidou, Kyriaki

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Breast Cancer, Genetics, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Female, Virulence, BRCA1 Protein, BRCA2 Protein, Ovarian Neoplasms, Genetic Predisposition to Disease, Breast Neoplasms, HEBON Investigators, GEMO Study Collaborators, AOCS Group, CZECANCA Consortium, Consortium of Investigators of Modifiers of BRCA1/2, Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.MethodsData for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).ResultsNo histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.ConclusionsWe provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Published
2023

30. Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study

Author

Ong, Jue-Sheng, Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Martin, Nicholas G, Chenevix-Trench, Georgia, Quinn, Michael CJ, Cornelis, Marilyn C, Gharahkhani, Puya, Webb, Penelope M, MacGregor, Stuart, Bryne, Enda, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Swerdlow, Anthony J, Jones, Michael, Orr, Nicholas, Schoemaker, Minouk, Edwards, Digna Velez, Brenton, James, Benítez, Javier, García, María J, Rodriguez-Antona, Cristina, Rossing, Mary Anne, Fortner, Renée T, Riboli, Elio, Chang-Claude, Jenny, Eilber, Ursula, Wang-Gohrke, Shan, Yannoukakos, Drakoulis, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Duerst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Heitz, Florian, Karlan, Beth, Olsson, Håkan, Kjaer, Susanne K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Hildebrandt, Michelle AT, Liang, Dong, Wu, Xifeng, Le Marchand, Loic, Setiawan, V Wendy, Permuth, Jennifer B, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Willet, Walter, Missmer, Stacey, Bjorge, Line, Kopperud, Reidun K, Bischof, Katharina, Thomsen, Liv Cecilie Vestrheim, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, and Lissowska, Jolanta

Subjects
Epidemiology, Health Sciences, Clinical Research, Ovarian Cancer, Nutrition, Rare Diseases, Prevention, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Coffee, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Ovarian Cancer Association Consortium, Statistics, Public Health and Health Services, Public health
Abstract

BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.

Published
2018

31. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author

Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Ngeow Yuen Yie, Joanne, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
Male, Risk, Urologic Diseases, Heterozygote, Aging, Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Rare Diseases, Breast Cancer, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Infant, Newborn, Ovarian Cancer, Pancreatic Neoplasms, Mutation, Female, Digestive Diseases
Abstract

PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Published
2022

32. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen, Colonna, Sarah, Lesueur, Fabienne, Mebirouk, Noura, Engel, Christoph, Schmutzler, Rita K., Davies, Eleanor, Eccles, Diana M., Evans, D. Gareth, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eliassen, Heather A., Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, van der Hout, Annemieke H., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Webb, Penelope M., Weinberg, Clarice R., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Lawrenson, Kate, deFazio, Anna, Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie M., Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Gayther, Simon A., Pharoah, Paul D. P., Claes, Kathleen B. M., Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Tung, Nadine, van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zavaglia, Katia M., Zorn, Kristin K., Sellers, Thomas A., Antoniou, Antonis C., Kleibl, Zdenek, Easton, Douglas, DeFazio, Anna, Cunningham, Julie, GEMO Study Collaborators, [missing], GC-HBOC Study Collaborators, [missing], EMBRACE Collaborators, [missing], OPAL Study Group, [missing], AOCS Group, [missing], KConFab Investigators, [missing], HEBON Investigators, [missing], The OCAC Consortium, [missing], The CIMBA Consortium, [missing], Clinicum, Department of Pathology, HUSLAB, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Faculteit Medische Wetenschappen/UMCG, Institut Català de la Salut, [Dareng EO, Barnes DR, Yang X] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK. [Tyrer JP] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK. [Jones MR] Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Aben KKH] Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ovarian Cancer Action, and National Institute for Health Research

Subjects
Male, Biochemistry & Molecular Biology, OCAC Consortium, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Breast Neoplasms, Ovaris - Càncer - Aspectes genètics, Carcinoma, Ovarian Epithelial, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, GEMO Study Collaborators, Risk Factors, OPAL Study Group, Other subheadings::Other subheadings::/genetics [Other subheadings], Medicine and Health Sciences, Genetics, Ovaris - Càncer - Propensió, Humans, Genetic Predisposition to Disease, Prospective Studies, EMBRACE Collaborators, GC-HBOC Study Collaborators, Genetics (clinical), HEBON Investigators, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Medicinsk genetik, Ovarian Neoplasms, Genetics & Heredity, 0604 Genetics, Science & Technology, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], 1103 Clinical Sciences, Bayes Theorem, AOCS Group, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Carcinoma, Ovarian Epithelial/genetics, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], CIMBA Consortium, 1182 Biochemistry, cell and molecular biology, Female, KConFab Investigators, Ovarian Neoplasms/epidemiology, Medical Genetics, Life Sciences & Biomedicine
Abstract

Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Published
2022

33. Identifying and testing for hereditary susceptibility to breast/ovarian cancer in Serbia: Where are we now?

Author

Branković-Magić Mirjana, Dobričić Jelena, Janković Radmila, Konstantopoulou Irene, Yannoukakos Drakoulis, and Radulović Siniša

Subjects
breast neoplasms, ovarian neoplasms, genes, BRCA2, genes, BRCA1, mutation, tumor markers, biological, genetic predisposition to diseases, non MeSH Serbia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia. .

Published
2006
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34. Genetically predicted DNA methylation biomarkers and epithelial ovarian cancer risk: data from nearly 63,000 women of European descent

Author

Yang, Yaohua, Wu, Lang, Shu, Xiang, Brenton, James D, Kar, Siddhartha, Tyrer, Jonathan P, White, Emily, Willett, Walter, Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul, Zheng, Wei, Long, Jirong, Brenton, James [0000-0002-5738-6683], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Risk, endocrine system diseases, 32 Biomedical and Clinical Sciences, Carcinoma, Ovarian Epithelial, 3105 Genetics, White People, Cohort Studies, Rare Diseases, Clinical Research, Predictive Value of Tests, Genetics, Biomarkers, Tumor, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Cancer, 2 Aetiology, Ovarian Neoplasms, Models, Genetic, Prevention, Human Genome, DNA Methylation, 3211 Oncology and Carcinogenesis, female genital diseases and pregnancy complications, Ovarian Cancer, FOS: Biological sciences, Women's Health, Female, 31 Biological Sciences
Abstract

Ovarian cancer is one of the most deadly cancers among women in the United States (1) and around the world (2). Approximately 90% of ovarian neoplasms are epithelial ovarian cancer (EOC) (1), a heterogeneous disease that can be categorized into five major histotypes (1). Genetic factors have an important impact on EOC etiology and large-scale genome-wide association studies (GWAS) have identified 34 common risk loci for EOC to date (3). Of these, 27 are specific to the most common histotype, serous EOC (3). Yet known loci are estimated to account for only a small proportion (~6.4%) of EOC risk (3). Further, causal genes at most loci and the underlying pathogenic mechanisms remain to be identified.

Published
2019
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35. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, Siddhartha P, Beesley, Jonathan, Amin Al Olama, Ali, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, ABCTB Investigators, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L

Subjects
AOCS Study Group & Australian Cancer Study, Male, Urologic Diseases, Aging, Enhancer Elements, Quantitative Trait Loci, Oncology and Carcinogenesis, ABCTB Investigators, Datasets as Topic, Breast Neoplasms, NBCS Investigators, APCB BioResource, PRACTICAL consortium, Rare Diseases, Meta-Analysis as Topic, Genetic, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Gene Regulatory Networks, Aetiology, Polymorphism, Cancer, Ovarian Neoplasms, Prostate Cancer, Human Genome, Prostatic Neoplasms, Chromosome Mapping, Single Nucleotide, Ovarian Cancer, Organ Specificity, Genetic Loci, Case-Control Studies, kConFab Investigators, Female, GENICA Network, Signal Transduction, Genome-Wide Association Study
Abstract

UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Published
2016

36. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author

Lawrenson, Kate, Kar, Siddhartha, McCue, Karen, Kuchenbaeker, Karoline, Michailidou, Kyriaki, Tyrer, Jonathan, Beesley, Jonathan, Ramus, Susan J., Li, Qiyuan, Delgado, Melissa K., Lee, Janet M., Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K., Arver, Brita, Bandera, Elisa V., Barile, Monica, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Benitez, Javier, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Blot, William, Bogdanova, Natalia, Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Børresen-Dale, Anne Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Bruinsma, Fiona, Brunet, Joan, Buhari, Shaik Ahmad, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Canniotto, Rikki, Chang-Claude, Jenny, Chiquette, Jocelyne, Choi, Ji Yeob, Claes, Kathleen B M, Cook, Linda S., Cox, Angela, Cramer, Daniel W., Cross, Simon S., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Dumont, Martine, Ehrencrona, Hans, Ejlertsen, Bent, Ellis, Steve, Engel, Christoph, Lee, Eunjung, Evans, D. Gareth, Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foretova, Lenka, Fostira, Florentia, Foulkes, William D., Fridley, Brooke L., Friedman, Eitan, Frost, Debra, Gambino, Gaetana, Ganz, Patricia A., Garber, Judy, García-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Ghoussaini, Maya, Giles, Graham G., Glasspool, Rosalind, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Goode, Ellen L., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A., Hall, Per, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V O, Harrington, Patricia A., Hartman, Mikael, Hassan, Norhashimah, Healey, Sue, Heitz, Florian, Herzog, Josef, Høgdall, Estrid, Høgdall, Claus K., Hogervorst, Frans B L, Hollestelle, Antoinette, Hopper, John L., Hulick, Peter J., Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Ito, Hidemi, Jakubowska, Anna, Janavicius, Ramunas, Jensen, Allan, John, Esther M., Johnson, Nichola, Kabisch, Maria, Kang, Daehee, Kapuscinski, Miroslav, Karlan, Beth Y., Khan, Sofia, Kiemeney, Lambertus A., Kjaer, Susanne Kruger, Knight, Julia A., Konstantopoulou, Irene, Kosma, Veli Matti, Kristensen, Vessela, Kupryjanczyk, Jolanta, Kwong, Ava, De La Hoya, Miguel, Laitman, Yael, Lambrechts, Diether, Le, Nhu, De Leeneer, Kim, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T., Lu, Karen, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Massuger, Leon F A G, Matsuo, Keitaro, Mazoyer, Sylvie, McGuffog, Lesley, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menon, Usha, Mensenkamp, Arjen R., Milne, Roger L., Montagna, Marco, Moysich, Kirsten B., Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Nord, Silje, Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olswold, Curtis, O'Malley, David, Orlow, Irene, Orr, Nick, Osorio, Ana, Park, Sue Kyung, Pearce, Celeste L., Pejovic, Tanja, Peterlongo, Paolo, Pfeiler, Georg, Phelan, Catherine M., Poole, Elizabeth M., Pylkäs, Katri, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad Usman, Rennert, Gad, Rhenius, Valerie, Rhiem, Kerstin, Risch, Harvey A., Rodriguez, Gus, Rossing, Mary Anne, Rudolph, Anja, Salvesen, Helga B., Sangrajrang, Suleeporn, Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Sellers, Thomas A., Seynaeve, Caroline, Shah, Mitul, Shen, Chen Yang, Shu, Xiao Ou, Sieh, Weiva, Singer, Christian F., Sinilnikova, Olga M., Slager, Susan, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stenmark-Askmalm, Marie, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony, Tchatchou, Sandrine, Teixeira, Manuel R., Teo, Soo H., Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Tibiletti, Maria Grazia, Tihomirova, Laima, Tognazzo, Silvia, Toland, Amanda Ewart, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tseng, Chiu Chen, Tung, Nadine, Tworoger, Shelley S., Vachon, Celine, Van Den Ouweland, Ans M W, Van Doorn, Helena C., Van Rensburg, Elizabeth J., Van't Veer, Laura J., Vanderstichele, Adriaan, Vergote, Ignace, Vijai, Joseph, Wang, Qin, Wang-Gohrke, Shan, Weitzel, Jeffrey N., Wentzensen, Nicolas, Whittemore, Alice S., Wildiers, Hans, Winqvist, Robert, Wu, Anna H., Yannoukakos, Drakoulis, Yoon, Sook Yee, Yu, Jyh Cherng, Zheng, Wei, Zheng, Ying, Khanna, Kum Kum, Simard, Jacques, Monteiro, Alvaro N., French, Juliet D., Couch, Fergus J., Freedman, Matthew L., Easton, Douglas F., Dunning, Alison M., Pharoah, Paul D., Edwards, Stacey L., Chenevix-Trench, Georgia, Antoniou, Antonis C., Gayther, Simon A., Bowtell, David, DeFazio, Anna, Webb, Penny, Collonge-Rame, Marie Agnès, Damette, Alexandre, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Ferrer, Sandra Fert, Bignon, Yves Jean, Uhrhammer, Nancy, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Leroux, Dominique, Dreyfus, Hélène, Rebischung, Christine, Peysselon, Magalie, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Adenis, Claude, Vénat-Bouvet, Laurence, Léone, Mélanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Verny-Pierre, Carole, Lasset, Christine, Bonadona, Valérie, Barjhoux, Laure, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Coupier, Isabelle, Pujol, Pascal, Sokolowska, Johanna, Bronner, Myriam, Delnatte, Capucine, Bézieau, Stéphane, Mari, Véronique, Gauthier-Villars, Marion, Buecher, Bruno, Rouleau, Etienne, Golmard, Lisa, Moncoutier, Virginie, Belotti, Muriel, De Pauw, Antoine, Elan, Camille, Fourme, Emmanuelle, Birot, Anne Marie, Saule, Claire, Laurent, Maïté, Houdayer, Claude, Lesueur, Fabienne, Mebirouk, Noura, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Muller, Danièle, Fricker, Jean Pierre, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Mortemousque, Isabelle, Bressac-De-Paillerets, Brigitte, Caron, Olivier, Guillaud-Bataille, Marine, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brady, Angela, Barwell, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Cook, Jackie, Snape, Katie, Murray, Alex, McCann, Emma, Rookus, M. A., Van Leeuwen, F. E., Van Der Kolk, L. E., Schmidt, M. K., Russell, N. S., De Lange, J. L., Wijnands, R., Collée, J. M., Hooning, M. J., Seynaeve, C., Van Deurzen, C. H M, Obdeijn, I. M., Van Asperen, C. J., Tollenaar, R. A E M, Van Cronenburg, T. C T E F, Kets, C. M., Ausems, M. G E M, Van Der Pol, C. C., Van Os, T. A M, Waisfisz, Q., Meijers-Heijboer, H. E J, Gómez-Garcia, E. B., Oosterwijk, J. C., Mourits, M. J., De Bock, G. H., Vasen, H. F., Siesling, S., Verloop, J., Overbeek, L. I H, Fox, Stephen, Kirk, Judy, Lindeman, Geoff, Price, Melanie, NIH - National Cancer Institute (NCI) (Estados Unidos), National Health and Medical Research Council (Australia), Victorian Health Promotion Foundation, Dutch Cancer Society (Holanda), Breast Cancer Research Trust, Instituto de Salud Carlos III, Lon V. Smith Foundation, Federal Ministry of Education & Research (Alemania), Finlands Akademi (Finlandia), United States Army Medical Research and Development Command, California Breast Cancer Research Program, German Cancer Aid, Canadian Institutes of Health Research, Ministère de Économie, Innovation et Exportation (Canadá), Ministry of Higher Education (Malasia), National Medical Research Council (Singapur), University of Oulu (Finlandia), Yorkshire Cancer Research, Hellenic Cooperative Oncology Group, California Cancer Research Program, Danish Cancer Society, Ministry of Science and Higher Education (Polonia), Asociación Española Contra el Cáncer, University of Kansas. Cancer Center (Estados Unidos), Hungarian Research Grants, Norwegian EEA Financial Mechanism, Canadian Breast Cancer Network, NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos), Congressionally Directed Medical Research Programs (Estados Unidos), NRG Oncology National (Estados Unidos), Unión Europea. Comisión Europea. 7 Programa Marco, Medical Oncology, Obstetrics & Gynecology, Clinical Genetics, 1 Department of Preventive Medicine, Keck School of MediCenter, Kansas City, Kansas 66160, USA. 90 Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel. 91 Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa 56126, Italy. 92 UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California 90024, USA. 93 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. 94 Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK. 95Women’s Cancer, UCL EGA Institute for Women’s Health, London WC1E 6AU, UK. 96 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. 97 Cancer Research UK Clinical Trials Unit, The BeatsonWest of Scotland Cancer Centre, Glasgow G12 0YN, UK. 98 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. 99 Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Que´bec H3A 1A1, Canada. 100 Department of Medicine, McGill University, Montreal, Que´bec H3A 1A1, Canada. 101 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. 102 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA. 103 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. 104Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. 105 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA. 106 Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland. 107 Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, 94805 Villejuif, France. 108 University Paris- Sud, 91405 Villejuif, France. 109 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 110 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark. 111 Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK. 112 Saw Swee Hock School of Public Health, National University of Singapore Singapore 119077, Singapore. 113 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia. 114 Cancer Research Initiatives Foundation, Subang Jaya, 47500 Selangor, Malaysia. 115 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany. 116 Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, 65199 Wiesbaden, Germany. 117 Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte California 91010, USA. 118 Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark. 119 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark. 120 Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark. 121 Family Cancer Clinic, Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands. 122 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands. 123 Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois 60201, USA. 124 N.N. Petrov Institute of Oncology, St Petersburg 197758, Russia. 125 Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia 20057, USA. 126 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan. 127 State Research Institute Centre for Innovative Medicine, LT-01102 Vilnius, Lithuania. 128 Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California 94538, USA. 129 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 08826, Korea. 130 Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia. 131Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. 132 Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500 Nijmegen, The Netherlands. 133 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. 134 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada. 135 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland. 136 Cancer Center, Kuopio University Hospital, 70210 Kuopio, Finland. 137 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210 Kuopio, Finland. 138 Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, 1478 Oslo, Norway. 139 The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China. 140 Department of Surgery, The University of Hong Kong, Hong Kong, China. 141Vesalius Research Center, VIB, 3000 Leuven, Belgium. 142 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium. 143 Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden. 144 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK. 145 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. 146 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), 20133 Milan, Italy. 147 University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA. 148 Department of Oncology - Pathology, Karolinska Institutet, SE- 171 77 Stockholm, Sweden. 149 National Center for Tumour Diseases, University of Heidelberg, 69117 Heidelberg, Germany. 150 Department of Gynaecology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands. 151 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan. 152 Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia. 153 Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. 154 Division of Gynaecology and Obstetrics, Technische Universita¨t Mu¨nchen, 81675 Munich, Germany. 155 Department of Human Genetics, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands. 156 Immunology and Molecular Oncology Unit, Instituto Oncologico Veneto IOV, IRCCS, 35128 Padua, Italy. 157 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. 158 Institute of Population Health, University of Manchester, Manchester M13 9PL, UK. 159 Laboratory Medicine Program, University Health Network, Toronto, Ontario M5G 1L7, Canada. 160 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L7, Canada. 161 The University of Texas School of Public Health, Houston, Texas 77030, USA. 162 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA. 163 Department of Medicine and Genetics, University of California, San Francisco, California 94143, USA. 164 Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. 165 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. 166 Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary. 167 Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois 60637, USA. 168 The Ohio State University and the James Cancer Center, Columbus, Ohio 43210, USA. 169 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York 10017, USA. 170 Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), 28019 Madrid, Spain. 171 Biomedical Network on Rare Diseases (CIBERER), 28029 Madrid, Spain. 172 Department of Surgery, Seoul National University College of Medicine, Seoul, 03080 Korea. 173 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA. 174 Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA. 175 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 16 20139 Milan, Italy. 176 Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. 177 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33606, USA. 178 Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 179 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts 02115, USA. 180 Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014 Oulu, Finland. 181 Laboratory of Cancer Genetics and Tumour Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland. 182 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT),cine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA. 2 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK. 3 QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia. 4 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK. 5 Medical College, Xiamen University, Xiamen 361102, China. 6 Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. 7 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00029 HUS, Finland. 8 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario Canada, M5G 1X5. 9 Department of Molecular Genetics, University of Toronto, Toronto, OntarioCanada, M5S 1A8. 10 Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA. 11 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany. 12 University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. 13 Department of Oncology, Karolinska University Hospital, Stockholm 171 77, Sweden. 14 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. 15 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan 20141, Italy. 16 Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik 600169- 2039, Iceland. 17 University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany. 18 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid E-28029, Spain. 19 Centro de Investigacio´n en Red de Enfermedades Raras, Valencia 28029, Spain. 20 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA. 21 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. 22 Department of Gynecology and Obstetrics, Haukeland University Hospital, 5021 Bergen, Norway. 23 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway. 24 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland. 25 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA. 26 International Epidemiology Institute, Rockville, Maryland 20850, USA. 27 Gynaecology Research Unit, Hannover Medical School, Hannover D-30625, Germany. 28 Department of Clinical Genetics, Vejle Hospital, Vejle 7100, Denmark. 29 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. 30 Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark. 31 Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark. 32 Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo N-0310, Norway. 33 K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo N-0310, Norway. 34 Dr Margarete Fischer- Bosch-Institute of Clinical Pharmacology, Stuttgart D-70376, Germany. 35 University of Tu¨bingen, Tu¨bingen 72074, Germany. 36 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 37 International Agency for Research on Cancer, Lyon 69008, France. 38 Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany. 39 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia. 40 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d’Investigacio´ Biome`dica de Girona), Catalan Institute of Oncology, Girona 08908, Spain. 41 Department of Surgery, National University Health System, Singapore 119077, Singapore. 42 Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 43 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany. 44 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland. 45 Department of Pathology, Helsinki University Central Hospital, Helsinki 00029, Finland. 46 Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA. 47 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigacio´n Sanitaria del Hospital Clı ´nico San Carlos), Madrid 28040, Spain. 48 Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. 49 Cancer Pathology & Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo 14263, New York, USA. 50 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany. 51 University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany. 52 Unite´ de recherche en sante´ des populations, Centre des maladies du sein Descheˆnes-Fabia, Centre de recherche FRSQ du Centre hospitalier affilie´ universitaire de Que´bec, Que´bec City, Que´bec Canada, G1J 1Z4. 53 Cancer Research Institute, Seoul National University, Seoul 08826, Korea. 54 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea. 55 Center for Medical Genetics, Ghent University, Ghent 9000, Belgium. 56 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA. 57 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield S10 2TN, UK. 58 Harvard HT Chan School of Public Health, Boston, Massachusetts 02115, USA. 59 Obstetrics and Gynecology Epidemiology Center, Brigham andWomen’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 60 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK. 61 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland. 62 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden. 63 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. 64 INSERM U1052, CNRS UMR5286, Universite´ Lyon, Centre de Recherche en Cance´rologie de Lyon, Lyon 69373, France. 65 Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology,Warsaw 44-101, Poland. 66 Department of Pathology, Leiden University Medical Center, Leiden 2333, The Netherlands. 67 Department of Human Genetics, Leiden University Medical Center, Leiden 2333, The Netherlands. 68 Oncogenetics Group, University Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO) and Universitat Auto`noma de Barcelona, Barcelona, 186 Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, 50931 Cologne, Germany. 187Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA. 188Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. 189 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. 190Department of Epidemiology, University of Washington, Seattle, Washington 98109, USA. 191National Cancer Institute, Bangkok 10400, Thailand. 192 Research Oncology, Guy’s Hospital, King’s College London, London SE1 9RT, UK. 193Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. 194 Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina 27710, USA. 195Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands. 196Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50676 Cologne, Germany. 197 Center for Integrated Oncology, University Hospital of Cologne, 50676 Cologne, Germany. 198 Center for Molecular Medicine, University Hospital of Cologne, 50676 Cologne, Germany. 199 Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, 50676 Cologne, Germany. 200 Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. 201 School of Public Health, China Medical University, Taichung 404, Taiwan. 202Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA. 203 Unite´ Mixte de Ge´ne´tique Constitutionnelle des Cancers Fre´quents, Hospices Civils de Lyon – Centre Le´on Be´rard, Lyon 69008, France. 204 INSERM U1052, CNRS UMR5286, Universite´ Lyon 1, Centre de Recherche en Cance´rologie de Lyon, Lyon 69003, France. 205Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia. 206Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linko¨ping University, 581 83 Linko¨ping, Sweden. 207 Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, 75248 Paris, France. 208Universite´ Paris Descartes, Sorbonne Paris Cite´, 75270 Paris, France. 209 Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany. 210Department of Genetics, Portuguese Oncology Institute, Porto 4200-072, Portugal. 211 Biomedical Sciences Institute (ICBAS), Porto University, Porto 4099-002, Portugal. 212Department of Epidemiology, Mailman School of Public Health, Columbia University, New York 10027, USA. 213Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark. 214UO Anatomia Patologica, Ospedale di Circolo-Universita` dell’Insubria, 21100 Varese, Italy. 215 Latvian Biomedical Research and Study Centre, Riga LV-1067, Latvia. 216 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), 64 - 35128 Padua, Italy. 217Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA. 218Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK. 219 Institute of Human Genetics, Pontificia Universidad Javeriana, Cra. 7 #40-62 Bogota, Colombia. 220Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. 221Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands. 222Department of Gynecology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands. 223Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium. 224University Hospital Ulm, 89069 Ulm, Germany. 225Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland 20892, USA. 226 Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium. 227 Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research ‘Demokritos’, Athens 153 10, Greece. 228 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia. 229 University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 59100 Kuala Lumpur, Malaysia. 230Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan. 231 Shanghai Center for Disease Control and Prevention, Shanghai, China. 232 Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA. 233Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. 234 Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. 235 Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia. 236 Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK. 237 Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia. 238 Department of Gynaecological Oncology, Westmead Institute for Cancer Research, Westmead Hospital Westmead, New South Wales 2145, Australia., Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Rhenius, Valerie [0000-0003-4215-3235], Song, Honglin [0000-0001-5076-7371], Wang, Jean [0000-0002-9139-0627], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Epidemiology and Data Science, EMGO - Quality of care, Anesthesiology, Human genetics, CCA - Cancer biology, and VU University medical center

Subjects
endocrine system diseases, Messenger, IDENTIFIES 3, MODIFIERS, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, GWAS, INVESTIGATORS, African Continental Ancestry Group, Asian Continental Ancestry Group, Breast Neoplasms, Chromosomes, Human, Pair 19, Female, Genome-Wide Association Study, Genotype, Humans, Ovarian Neoplasms, RNA, Messenger, Alleles, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, skin and connective tissue diseases, COMMON VARIANTS, EPITHELIAL-CELLS, Single Nucleotide, female genital diseases and pregnancy complications, NAF12, Medical Genetics, Human, endocrine system, Science, Chromosomes, Human, Pair 19/genetics, Black People, Breast Neoplasms/genetics, Chromosomes, Article, Ovarian Neoplasms/genetics, SDG 3 - Good Health and Well-being, Asian People, REVEALS, Polymorphism, GENOME-WIDE ASSOCIATION, Krabbamein, Medicinsk genetik, Cancer och onkologi, Pair 19, Arfgengi, GENE, Eggjastokkar, Cancer and Oncology, RNA, BRCA1 Protein/genetics
Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P, A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Published
2016

37. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author

Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen Bm, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Australian Ovarian Cancer Study Group, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei, Hunter, David J, Lindstrom, Sara, Hankinson, Susan E, Kraft, Peter, Andrulis, Irene, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Jukkola-Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert AEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M, Rafiq, Sajjad, Tapper, William J, Gerty, Sue M, Hooning, Maartje J, Martens, John WM, Collée, J Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Cox, Angela, Reed, Malcolm WR, Luccarini, Craig, Baynes, Caroline, Dunning, Alison M, Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rüdiger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E, Ambrosone, Christine B, Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Álvarez, Nuria, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Børge G, Weischer, Maren, Travis, Ruth C, Neal, David, Donovan, Jenny L, Hamdy, Freddie C, Khaw, Kay-Tee, Stanford, Janet L, Blot, William J, Thibodeau, Stephen, Schaid, Daniel J, Kelley, Joseph L, Maier, Christiane, Kibel, Adam S, Cybulski, Cezary, Cannon-Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R, Kote-Jarai, Zsofia, Olama, Ali Amin Al, Benlloch, Sara, Renner, Stefan P, Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang-Gohrke, Shan, Odunsi, Kunle, Sucheston-Campbell, Lara E, Friel, Grace, Lurie, Galina, Killeen, Jeffrey L, Wilkens, Lynne R, Goodman, Marc T, Runnebaum, Ingo, Hillemanns, Peter A, Pelttari, Liisa M, Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Moysich, Kirsten B, du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Larson, Melissa C, Fogarty, Zachary C, Kalli, Kimberly R, Liang, Dong, Lu, Karen H, Hildebrandt, Michelle AT, Wu, Xifeng, Levine, Douglas A, Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S, Marks, Jeffrey R, Akushevich, Lucy, Cramer, Daniel W, Schildkraut, Joellen, Terry, Kathryn L, Poole, Elizabeth M, Stampfer, Meir, Tworoger, Shelley S, Bandera, Elisa V, Orlow, Irene, Olson, Sara H, Bjorge, Line, Salvesen, Helga B, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie, Brooks-Wilson, Angela, Kelemen, Linda E, Cook, Linda S, Le, Nhu D, Górski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Høgdall, Claus K, Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T, Sutphen, Rebecca, McLaughlin, John R, Narod, Steven A, Phelan, Catherine M, Monteiro, Alvaro N, Fenstermacher, David, Lin, Hui-Yi, Permuth, Jennifer B, Sellers, Thomas A, Chen, Y Ann, Tsai, Ya-Yu, Chen, Zhihua, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Menon, Usha, Wu, Anna H, Pearce, Celeste L, Van Den Berg, David, Pike, Malcolm C, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Moes-Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul Dp, Song, Honglin, Winship, Ingrid, Chenevix-Trench, Georgia, Giles, Graham G, Tavtigian, Sean V, Easton, Doug F, Milne, Roger L, Clinical Genetics, Neurology, Medical Oncology, Surgery, Erasmus MC other, Clinicum, Department of Obstetrics and Gynecology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, Department of Pathology, HUS Gynecology and Obstetrics, Tischkowitz, Marc [0000-0002-7880-0628], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Khaw, Kay-Tee [0000-0002-8802-2903], Amin Al Olama, Ali [0000-0002-7178-3431], Dicks, Ed [0000-0002-0617-0401], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Song, Honglin [0000-0001-5076-7371], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Ataxia Telangiectasia Mutated Proteins, prostate-cancer, Prostate cancer, 0302 clinical medicine, brca1, Medizinische Fakultät, Medicine and Health Sciences, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, brca2-interacting protein, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], 1184 Genetics, developmental biology, physiology, Nuclear Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, PROSTATE-CANCER, Cancer: prostate, Multicenter Study, ovarian-cancer, Centre for Surgical Research, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, ovary [Cancer], Female, Fanconi Anemia Complementation Group N Protein, metaanalysis, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, 3122 Cancers, cancer predisposition, Breast Neoplasms, OVARIAN-CANCER, BRCA2-INTERACTING PROTEIN, Cancer: ovary, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, prostate [Cancer], medicine, Cancer Genetics, Genetics, Journal Article, breast [Cancer], BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, education, gene, CHEK2, FAMILY REGISTRY, METAANALYSIS, breast-cancer, Genetic Association Studies, business.industry, MUTATIONS, Cancer: breast, Tumor Suppressor Proteins, Case-control study, Cancer, Prostatic Neoplasms, medicine.disease, BRCA1, mutations, GENE, susceptibility loci, Checkpoint Kinase 2, 030104 developmental biology, Relative risk, Case-Control Studies, Mutation, family registry, Ovarian cancer, business
Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

38. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Osorio, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco Guillermo, Ignacio, De la Hoya, Miguel, Durán, Mercedes, Diez, Orland, Ramon y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, None, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I., Beattie, Mary S., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John L, Terry, Mary Beth, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas v. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana M, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jörg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Claes, Kathleen, Piedmonte, Marion, Tucker, Kathy, Backes, Floor, Rodríguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Rookus, Matti A., van Os, Theo A. M., van der Kolk, Lizet, de Lange, J. L., Meijers-Heijboer, Hanne E. J., van der Hout, A. H., van Asperen, Christi J., Gómez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collée, J. Margriet, van Deurzen, Carolien H. M., van der Luijt, Rob B., Devilee, Peter, HEBON, None, Olah, Edith, Lázaro, Conxi, Teulé, Alex, Menéndez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Johannsson, Oskar Th., Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Investigators, kConFab, Olswold, Curtis, Guidugli, Lucia, Lindor, Noralane, Slager, Susan, Szabo, Csilla I., Vijai, Joseph, Robson, Mark, Kauff, Noah, Zhang, Liying, Rau-Murthy, Rohini, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Geschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Berger, Andreas, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Lejbkowicz, Flavio, Andrulis, Irene L., Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, Universitat Autònoma de Barcelona, Pediatric Surgery, Clinical Genetics, Pathology, Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 2Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 5Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain. 6IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. 7Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 9Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain. 10Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain. 11Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 12Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece. 13Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain. 14Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain. 15Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 16Department of Oncology, Lund University, Lund, Sweden. 17Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. 18Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 19Department of Oncology, Lund University Hospital, Lund, Sweden. 20Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 21Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America. 22Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America. 23Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. 24Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. 25University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 26Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. 27Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America. 28Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America. 29Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America. 30Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia. 31Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia. 32Department of Epidemiology, Columbia University, New York, New York, United States of America. 33Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. 34Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania. 35Department of Genetics, University of Pretoria, Pretoria, South Africa. 36Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America. 37Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 39Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 40Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America. 41Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 42Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 43IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 44Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 45Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 46Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 47Department of Molecular Medicine, 'Sapienza' University, Rome, Italy. 48UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy. 49Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 50Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 51Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 52South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom. 53Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom. 54Yorkshire Regional Genetics Service, Leeds, United Kingdom. 55Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom. 56West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom. 57Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 58Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom. 59Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom. 60Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 61Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom. 62Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 63South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom. 64North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 65Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom. 66Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom. 67South West Regional Genetics Service, Bristol, United Kingdom. 68Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire. 69Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom. 70Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America. 71Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. 72Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 73Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 74Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 75Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 76Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 77Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 78Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 79Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 80Institute of Human Genetics, University of Münster, Münster, Germany. 81Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 82Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany. 83Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany. 84Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 85Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 86INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 87Center for Medical Genetics, Ghent University, Ghent, Belgium. 88Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America. 89Prince of Wales Hospital. Sydney, Australia. 90Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America. 91Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America. 92Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America. 93For Tufts Medical Center, Boston, Massachusetts, United States of America. 94Yale University School of Medicine, New Haven, Connecticut, United States of America. 95Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 96Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 97Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 98Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands. 99Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 100University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 101Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands. 102Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands. 103Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 104Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 105Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 106Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 107Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 108The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands. 109Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 110Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 111Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 112Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland. 113Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland. 114Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France. 115Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 116Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 117Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia. 118Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia. 119Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. 120Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 121Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America. 122Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America. 123Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 124Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 125Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 126Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 127Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. 128Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America. 129Clalit National Israeli Cancer Control Center, Haifa, Israel. 130Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 131Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 132Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 133Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America. 134Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 135Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 136Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 137Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 138Sheba Medical Center, Tel Aviv, Israel. 139Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 140Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 141Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain, Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain., SWE-BRCA, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Unión Europea, Cancer Research UK (Reino Unido), United States of Department of Health & Human Services, Canadian Institutes of Health Research, Susan G. Komen Breast Cancer Foundation, Ralph and Marion Falk Medical Research Trust, Research Council (Lituania), University of Kansas. Cancer Center (Estados Unidos), National Institute for Health Research (Reino Unido), Deutsche Krebshilfe, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Hungarian Scientific Research Fund (Hungría), Canadian Breast Cancer Network, Ministère du Développement économique, de Innovation et de Exportation (Canadá), Westat (Estados Unidos), Department of Obstetrics and Gynecology, Clinicum, Universitat de Barcelona, Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, CCA - Oncogenesis, Fundación Mutua Madrileña Automovilista, Fundacion Asociacion Espanola Contra el Cancer (AECC), Instituto de Salud Carlos III - ISCIII, European Union (EU), Cancer Research UK, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Canadian Institutes of Health Research (CIHR), Research Council of Lithuania, University of Kansas Cancer Center, National Institute for Health Research (NIHR), Academy of Finland, KWF Kankerbestrijding, Netherlands Organization for Scientific Research (NWO), Pink Ribbon grant, Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA), Canadian Breast Cancer Research Alliance-grant, Ministry of Economic Development, Innovation and Export Trade, and Westat, Inc, Rockville, MD

Subjects
Cancer Research, 24 Ciencias de la Vida, DNA Repair, endocrine system diseases, ADN, Càncer d'ovari, Synthetic lethality, BRCA1 Protein/genetics, DNA Glycosylases, 0302 clinical medicine, DNA Glycosylases/genetics, Brjóstakrabbamein, Genotype, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Glicosilasas, INVESTIGATORS, skin and connective tissue diseases, OGG1, Genetics (clinical), Genetics, DAMAGE, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, SINGLE-NUCLEOTIDE POLYMORPHISMS, COMMON VARIANTS, Base excision repair, Middle Aged, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, NEIL2, Female, Medical Genetics, Research Article, BRCA1, BRCA2, Adult, Risk, Ovarian Neoplasms/genetics, lcsh:QH426-470, Adolescent, DNA repair, education, Single-nucleotide polymorphism, Breast Neoplasms, DNA Repair/genetics, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Polymorphism, Single Nucleotide/genetics, SDG 3 - Good Health and Well-being, Ovarian cancer, Cancer Genetics, BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, BRCA2 Protein/genetics, CONSORTIUM, Biology and Life Sciences, Arfgengi, lcsh:Genetics, DNA glycosylase, Cancer research, 3111 Biomedicine, GENETIC MODIFIERS, Genètica
Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p, Author Summary Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.

Published
2014

39. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

Author

Couch, Fergus J, Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B, Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M, Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M, Lee, Adam, Bacot, François, Vincent, Daniel, Hogervorst, Frans BL, Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, kConFab Investigators, Radice, Paolo, Schmutzler, Rita Katharina, SWE-BRCA, Domchek, Susan M, Piedmonte, Marion, Singer, Christian F, Friedman, Eitan, Thomassen, Mads, Ontario Cancer Genetics Network, Hansen, Thomas VO, Neuhausen, Susan L, Szabo, Csilla I, Blanco, Ignacio, Greene, Mark H, Karlan, Beth Y, Garber, Judy, Phelan, Catherine M, Weitzel, Jeffrey N, Montagna, Marco, Olah, Edith, Andrulis, Irene L, Godwin, Andrew K, Yannoukakos, Drakoulis, Goldgar, David E, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B, van Rensburg, Elizabeth J, Hamann, Ute, Ramus, Susan J, Toland, Amanda Ewart, Caligo, Maria A, Olopade, Olufunmilayo I, Tung, Nadine, Claes, Kathleen, Beattie, Mary S, Southey, Melissa C, Imyanitov, Evgeny N, Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M, Kwong, Ava, Diez, Orland, Balmaña, Judith, Barkardottir, Rosa B, Arun, Banu K, Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A, Campbell, Ian, van der Hout, Annemarie H, van Deurzen, Carolien HM, Seynaeve, Caroline, Gómez Garcia, Encarna B, van Leeuwen, Flora E, Meijers-Heijboer, Hanne EJ, Gille, Johannes JP, Ausems, Margreet GEM, Blok, Marinus J, Ligtenberg, Marjolijn JL, Rookus, Matti A, Devilee, Peter, Verhoef, Senno, van Os, Theo AM, Wijnen, Juul T, HEBON, EMBRACE, Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D Gareth, Izatt, Louise, Eeles, Rosalind A, Adlard, Julian, and Hunter, Kent W

Subjects
Heterozygote, endocrine system diseases, Genotype, Breast Neoplasms, EMBRACE, GEMO Study Collaborators, Rare Diseases, Risk Factors, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Polymorphism, skin and connective tissue diseases, HEBON, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Human Genome, BCFR, Single Nucleotide, SWE-BRCA, Middle Aged, Prognosis, Ovarian Cancer, Mutation, kConFab Investigators, Female, CIMBA, Ontario Cancer Genetics Network, Genome-Wide Association Study, Developmental Biology
Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Published
2013

40. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author

Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, Van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen Bm, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, KConFab, Australian Ovarian Cancer Study Group, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei, Hunter, David J, Lindstrom, Sara, Hankinson, Susan E, Kraft, Peter, Andrulis, Irene, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Jukkola-Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert AEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M, Rafiq, Sajjad, Tapper, William J, Gerty, Sue M, Hooning, Maartje J, Martens, John WM, Collée, J Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Cox, Angela, Reed, Malcolm WR, Luccarini, Craig, Baynes, Caroline, Dunning, Alison M, Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rüdiger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E, Ambrosone, Christine B, Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Álvarez, Nuria, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Børge G, Weischer, Maren, Travis, Ruth C, Neal, David, Donovan, Jenny L, Hamdy, Freddie C, Khaw, Kay-Tee, Stanford, Janet L, Blot, William J, Thibodeau, Stephen, Schaid, Daniel J, Kelley, Joseph L, Maier, Christiane, Kibel, Adam S, Cybulski, Cezary, Cannon-Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R, Kote-Jarai, Zsofia, Olama, Ali Amin Al, Benlloch, Sara, Renner, Stefan P, Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang-Gohrke, Shan, Odunsi, Kunle, Sucheston-Campbell, Lara E, Friel, Grace, Lurie, Galina, Killeen, Jeffrey L, Wilkens, Lynne R, Goodman, Marc T, Runnebaum, Ingo, Hillemanns, Peter A, Pelttari, Liisa M, Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Moysich, Kirsten B, Du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Larson, Melissa C, Fogarty, Zachary C, Kalli, Kimberly R, Liang, Dong, Lu, Karen H, Hildebrandt, Michelle AT, Wu, Xifeng, Levine, Douglas A, Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S, Marks, Jeffrey R, Akushevich, Lucy, Cramer, Daniel W, Schildkraut, Joellen, Terry, Kathryn L, Poole, Elizabeth M, Stampfer, Meir, Tworoger, Shelley S, Bandera, Elisa V, Orlow, Irene, Olson, Sara H, Bjorge, Line, Salvesen, Helga B, Van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie, Brooks-Wilson, Angela, Kelemen, Linda E, Cook, Linda S, Le, Nhu D, Górski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Høgdall, Claus K, Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T, Sutphen, Rebecca, McLaughlin, John R, Narod, Steven A, Phelan, Catherine M, Monteiro, Alvaro N, Fenstermacher, David, Lin, Hui-Yi, Permuth, Jennifer B, Sellers, Thomas A, Chen, Y Ann, Tsai, Ya-Yu, Chen, Zhihua, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Menon, Usha, Wu, Anna H, Pearce, Celeste L, Van Den Berg, David, Pike, Malcolm C, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Moes-Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul Dp, Song, Honglin, Winship, Ingrid, Chenevix-Trench, Georgia, Giles, Graham G, Tavtigian, Sean V, Easton, Doug F, and Milne, Roger L

Subjects
Male, Ovarian Neoplasms, Risk, Cancer: breast, Tumor Suppressor Proteins, cancer predisposition, Nuclear Proteins, Prostatic Neoplasms, Breast Neoplasms, Ataxia Telangiectasia Mutated Proteins, 3. Good health, Cancer: prostate, Cancer: ovary, Checkpoint Kinase 2, FOS: Biological sciences, Case-Control Studies, Mutation, Genetics, Humans, Female, Genetic Predisposition to Disease, Fanconi Anemia Complementation Group N Protein, Genetic Association Studies
Abstract

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

41. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, Siddhartha P, Beesley, Jonathan, Amin Al Olama, Ali, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, ABCTB Investigators, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, Hopper, John L, Kupryjanczyk, Jolanta, Park, Jong Y, Figueroa, Jonine, Clements, Judith A, Knight, Julia A, Peto, Julian, Cunningham, Julie M, Pow-Sang, Julio, Batra, Jyotsna, Czene, Kamila, Lu, Karen H, Herkommer, Kathleen, Khaw, Kay-Tee, KConFab Investigators, Matsuo, Keitaro, Muir, Kenneth, Offitt, Kenneth, Chen, Kexin, Moysich, Kirsten B, Aittomäki, Kristiina, Odunsi, Kunle, Kiemeney, Lambertus A, Massuger, Leon FAG, Fitzgerald, Liesel M, Cook, Linda S, Cannon-Albright, Lisa, Hooning, Maartje J, Pike, Malcolm C, Bolla, Manjeet K, Luedeke, Manuel, Teixeira, Manuel R, Goodman, Marc T, Schmidt, Marjanka K, Riggan, Marjorie, Aly, Markus, Rossing, Mary Anne, Beckmann, Matthias W, Moisse, Matthieu, Sanderson, Maureen, Southey, Melissa C, Jones, Michael, Lush, Michael, Hildebrandt, Michelle AT, Hou, Ming-Feng, Schoemaker, Minouk J, Garcia-Closas, Montserrat, Bogdanova, Natalia, Rahman, Nazneen, NBCS Investigators, Le, Nhu D, Orr, Nick, Wentzensen, Nicolas, Pashayan, Nora, Peterlongo, Paolo, Guénel, Pascal, Brennan, Paul, Paulo, Paula, Webb, Penelope M, Broberg, Per, Fasching, Peter A, Devilee, Peter, Wang, Qin, Cai, Qiuyin, Li, Qiyuan, Kaneva, Radka, Butzow, Ralf, Kopperud, Reidun Kristin, Schmutzler, Rita K, Stephenson, Robert A, MacInnis, Robert J, Hoover, Robert N, Winqvist, Robert, Ness, Roberta, Milne, Roger L, Travis, Ruth C, Benlloch, Sara, Olson, Sara H, McDonnell, Shannon K, Tworoger, Shelley S, Maia, Sofia, Berndt, Sonja, Lee, Soo Chin, Teo, Soo-Hwang, Thibodeau, Stephen N, Bojesen, Stig E, Gapstur, Susan M, Kjær, Susanne Krüger, Pejovic, Tanja, Tammela, Teuvo LJ, GENICA Network, PRACTICAL Consortium, Dörk, Thilo, Brüning, Thomas, Wahlfors, Tiina, Key, Tim J, Edwards, Todd L, Menon, Usha, Hamann, Ute, Mitev, Vanio, Kosma, Veli-Matti, Setiawan, Veronica Wendy, Kristensen, Vessela, Arndt, Volker, Vogel, Walther, Zheng, Wei, Sieh, Weiva, Blot, William J, Kluzniak, Wojciech, Shu, Xiao-Ou, Gao, Yu-Tang, Schumacher, Fredrick, Freedman, Matthew L, Berchuck, Andrew, Dunning, Alison M, Simard, Jacques, Haiman, Christopher A, Spurdle, Amanda, Sellers, Thomas A, Hunter, David J, Henderson, Brian E, Kraft, Peter, Chanock, Stephen J, Couch, Fergus J, Hall, Per, Gayther, Simon A, Easton, Douglas F, Chenevix-Trench, Georgia, Eeles, Rosalind, Pharoah, Paul DP, and Lambrechts, Diether

Subjects
Male, Ovarian Neoplasms, Quantitative Trait Loci, Chromosome Mapping, Datasets as Topic, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Enhancer Elements, Genetic, Meta-Analysis as Topic, Genetic Loci, Organ Specificity, Case-Control Studies, Humans, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Signal Transduction
Abstract

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

42. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Author

Qian, Frank, Rookus, Matti A, Leslie, Goska, Risch, Harvey A, Greene, Mark H, Aalfs, Cora M, Adank, Muriel A, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arnold, Norbert, Arun, Banu K, Ausems, Margreet GEM, Azzollini, Jacopo, Barrowdale, Daniel, Barwell, Julian, Benitez, Javier, Białkowska, Katarzyna, Bonadona, Valérie, Borde, Julika, Borg, Ake, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Carter, Jonathan, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Collée, J Margriet, Collonge-Rame, Marie-Agnès, Couch, Fergus J, Daly, Mary B, Delnatte, Capucine, Diez, Orland, Domchek, Susan M, Dorfling, Cecilia M, Eason, Jacqueline, Easton, Douglas F, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Feliubadaló, Lidia, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Garcia-Barberan, Vanesa, Gehrig, Andrea, Glendon, Gord, Godwin, Andrew K, Gómez Garcia, Encarna B, Hamann, Ute, Hauke, Jan, Hopper, John L, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Jakubowska, Anna, Janavicius, Ramunas, John, Esther M, Karlan, Beth Y, Kets, Carolien M, Laitman, Yael, Lázaro, Conxi, Leroux, Dominique, Lester, Jenny, Lesueur, Fabienne, Loud, Jennifer T, Lubiński, Jan, Łukomska, Alicja, McGuffog, Lesley, Mebirouk, Noura, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Miller, Austin, Montagna, Marco, Mooij, Thea M, Mouret-Fourme, Emmanuelle, Nathanson, Katherine L, Nehoray, Bita, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Offit, Kenneth, Olah, Edith, Ong, Kai-Ren, Oosterwijk, Jan C, Ottini, Laura, Parsons, Michael T, Peterlongo, Paolo, Pfeiler, Georg, Pradhan, Nisha, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rennert, Gad, Robson, Mark, Rodriguez, Gustavo C, Salani, Ritu, Scheuner, Maren T, Schmutzler, Rita K, Shah, Payal D, Side, Lucy E, Simard, Jacques, Singer, Christian F, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Tan, Yen Yen, Teixeira, Manuel R, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E, Tung, Nadine, Van Asperen, Christi J, Van Engelen, Klaartje, Van Rensburg, Elizabeth J, Venat-Bouvet, Laurence, Vierstraete, Jeroen, Wagner, Gabriel, Walker, Lisa, Weitzel, Jeffrey N, Yannoukakos, Drakoulis, KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, Antoniou, Antonis C, Goldgar, David E, Olopade, Olufunmilayo I, Chenevix-Trench, Georgia, Rebbeck, Timothy R, Huo, Dezheng, and CIMBA

Subjects
2. Zero hunger, Adult, Ovarian Neoplasms, Heterozygote, Genes, BRCA2, Genes, BRCA1, Mendelian Randomization Analysis, Middle Aged, Body Height, 3. Good health, Body Mass Index, Mutation, Humans, Female, Menopause, Aged, Proportional Hazards Models
Abstract

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

43. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author

Barnes, Daniel R, Rookus, Matti A, McGuffog, Lesley, Leslie, Goska, Mooij, Thea M, Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L, Arnold, Norbert, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M, Blok, Marinus J, Bonanni, Bernardo, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Bradbury, Angela R, Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K, Claes, Kathleen BM, Colas, Chrystelle, GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B, Davidson, Rosemarie, De La Hoya, Miguel, De Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dorfling, Cecilia M, Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans BL, Hooning, Maartje J, Horvath, Judit, Hu, Chunling, Hulick, Peter J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, GENEPSO Investigators, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kast, Karin, Koudijs, Marco, Kruse, Torben A, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loud, Jennifer T, Lubiński, Jan, Mai, Phuong L, Manoukian, Siranoush, Mari, Véronique, Mebirouk, Noura, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Mensenkamp, Arjen R, Miller, Austin, Montagna, Marco, Mouret-Fourme, Emmanuelle, Mukherjee, Semanti, Mulligan, Anna Marie, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Noguès, Catherine, Olah, Edith, Olopade, Olufunmilayo I, Ong, Kai-Ren, O'Shaughnessy-Kirwan, Aoife, Osorio, Ana, Ott, Claus-Eric, Papi, Laura, Park, Sue K, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Peterlongo, Paolo, Pfeiler, Georg, Phillips, Kelly-Anne, Prajzendanc, Karolina, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rennert, Gad, Risch, Harvey A, Robson, Mark, Rønlund, Karina, Salani, Ritu, Schuster, Hélène, Senter, Leigha, Shah, Payal D, Sharma, Priyanka, Side, Lucy E, Singer, Christian F, Slavin, Thomas P, Soucy, Penny, Southey, Melissa C, Spurdle, Amanda B, Steinemann, Doris, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Thull, Darcy L, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E, Trainer, Alison H, Tung, Nadine, Van Engelen, Klaartje, Van Rensburg, Elizabeth J, Vega, Ana, Vierstraete, Jeroen, Wagner, Gabriel, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Yadav, Siddhartha, Yang, Xin, Yannoukakos, Drakoulis, Zimbalatti, Dario, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, and Consortium Of Investigators Of Modifiers Of BRCA And BRCA2

Subjects
BRCA2 Protein, Ovarian Neoplasms, Heterozygote, endocrine system diseases, BRCA1 Protein, Breast Neoplasms, Carcinoma, Ovarian Epithelial, PRS, 3. Good health, breast cancer, ovarian cancer, BRCA1/2, Risk Factors, Mutation, Humans, genetics, Female, Genetic Predisposition to Disease, Prospective Studies, Retrospective Studies
Abstract

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

44. Shared heritability and functional enrichment across six solid cancers

Author

Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, DeFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, Ganz, Patricia A, Garber, Judy, García-Sáenz, José A, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, Goode, Ellen L, Goodman, Marc T, Goodman, Gary, Grankvist, Kjell, Greene, Mark H, Gronberg, Henrik, Gronwald, Jacek, Guénel, Pascal, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hamdy, Freddie C, Hamilton, Robert J, Hampe, Jochen, Haugen, Aage, Heitz, Florian, Herrero, Rolando, Hillemanns, Peter, Hoffmeister, Michael, Høgdall, Estrid, Hong, Yun-Chul, Hopper, John L, Houlston, Richard, Hulick, Peter J, Hunter, David J, Huntsman, David G, Idos, Gregory, Imyanitov, Evgeny N, Ingles, Sue Ann, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Jenkins, Mark A, Johansson, Mattias, Johansson, Mikael, John, Esther M, Joshi, Amit D, Kaneva, Radka, Karlan, Beth Y, Kelemen, Linda E, Kühl, Tabea, Khaw, Kay-Tee, Khusnutdinova, Elza, Kibel, Adam S, Kiemeney, Lambertus A, Kim, Jeri, Kjaer, Susanne K, Knight, Julia A, Kogevinas, Manolis, Kote-Jarai, Zsofia, Koutros, Stella, Kristensen, Vessela N, Kupryjanczyk, Jolanta, Lacko, Martin, Lam, Stephan, Lambrechts, Diether, Landi, Maria Teresa, Lazarus, Philip, Le, Nhu D, Lee, Eunjung, Lejbkowicz, Flavio, Lenz, Heinz-Josef, Leslie, Goska, Lessel, Davor, Lester, Jenny, Levine, Douglas A, Li, Li, Li, Christopher I, Lindblom, Annika, Lindor, Noralane M, Liu, Geoffrey, Loupakis, Fotios, Lubiński, Jan, Maehle, Lovise, Maier, Christiane, Mannermaa, Arto, Marchand, Loic Le, Margolin, Sara, May, Taymaa, McGuffog, Lesley, Meindl, Alfons, Middha, Pooja, Miller, Austin, Milne, Roger L, MacInnis, Robert J, Modugno, Francesmary, Montagna, Marco, Moreno, Victor, Moysich, Kirsten B, Mucci, Lorelei, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L, Neal, David E, Ness, Andrew R, Neuhausen, Susan L, Nevanlinna, Heli, Newcomb, Polly A, Newcomb, Lisa F, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Nordestgaard, Børge G, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olama, Ali Amin Al, Olopade, Olufunmilayo I, Olshan, Andrew F, Olsson, Håkan, Osorio, Ana, Pandha, Hardev, Park, Jong Y, Pashayan, Nora, Parsons, Michael T, Pejovic, Tanja, Penney, Kathryn L, Peters, Wilbert HM, Phelan, Catherine M, Phipps, Amanda I, Plaseska-Karanfilska, Dijana, Pring, Miranda, Prokofyeva, Darya, Radice, Paolo, Stefansson, Kari, Ramus, Susan J, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Van Rensburg, Elizabeth J, Riggan, Marjorie J, Risch, Harvey A, Risch, Angela, Roobol, Monique J, Rosenstein, Barry S, Rossing, Mary Anne, De Ruyck, Kim, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schabath, Matthew B, Schleutker, Johanna, Schmidt, Marjanka K, Setiawan, V Wendy, Shen, Hongbing, Siegel, Erin M, Sieh, Weiva, Singer, Christian F, Slattery, Martha L, Sorensen, Karina Dalsgaard, Southey, Melissa C, Spurdle, Amanda B, Stanford, Janet L, Stevens, Victoria L, Stintzing, Sebastian, Stone, Jennifer, Sundfeldt, Karin, Sutphen, Rebecca, Swerdlow, Anthony J, Tajara, Eloiza H, Tangen, Catherine M, Tardon, Adonina, Taylor, Jack A, Teare, M Dawn, Teixeira, Manuel R, Terry, Mary Beth, Terry, Kathryn L, Thibodeau, Stephen N, Thomassen, Mads, Bjørge, Line, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Townsend, Paul A, Travis, Ruth C, Tung, Nadine, Tworoger, Shelley S, Ulrich, Cornelia M, Usmani, Nawaid, Vachon, Celine M, Van Nieuwenhuysen, Els, Vega, Ana, Aguado-Barrera, Miguel Elías, Wang, Qin, Webb, Penelope M, Weinberg, Clarice R, Weinstein, Stephanie, Weissler, Mark C, Weitzel, Jeffrey N, West, Catharine ML, White, Emily, Whittemore, Alice S, Wichmann, H-Erich, Wiklund, Fredrik, Winqvist, Robert, Wolk, Alicja, Woll, Penella, Woods, Michael, Wu, Anna H, Wu, Xifeng, Yannoukakos, Drakoulis, Zheng, Wei, Zienolddiny, Shanbeh, Ziogas, Argyrios, Zorn, Kristin K, Lane, Jacqueline M, Saxena, Richa, Thomas, Duncan, Hung, Rayjean J, Diergaarde, Brenda, McKay, James, Peters, Ulrike, Hsu, Li, García-Closas, Montserrat, Eeles, Rosalind A, Chenevix-Trench, Georgia, Brennan, Paul J, Haiman, Christopher A, Simard, Jacques, Easton, Douglas F, Gruber, Stephen B, Pharoah, Paul DP, Price, Alkes L, Pasaniuc, Bogdan, Amos, Christopher I, Kraft, Peter, and Lindström, Sara

Subjects
Male, Ovarian Neoplasms, Lung Neoplasms, Mental Disorders, Smoking, Inheritance Patterns, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 3. Good health, Neoplasm Proteins, Phenotype, Head and Neck Neoplasms, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

45. Shared heritability and functional enrichment across six solid cancers

Author

Graham G. Giles, Diana Eccles, Cezary Cybulski, Catherine M. Tangen, Leon Raskin, Per Hall, Ana Vega, Hedy S. Rennert, Andrew T. Chan, Stephan Lam, Michael Hoffmeister, Angeline S. Andrew, Claudine Isaacs, Matthias W. Beckmann, Vessela N. Kristensen, Julia A. Knight, Mark S. Goldberg, Jonathan Tyrer, Jane C. Figueiredo, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Nora Pashayan, Liene Nikitina-Zake, Goska Leslie, Rosalind A. Eeles, Line Bjørge, Adonina Tardón, Angela Cox, Gregory Idos, Evgeny N. Imyanitov, Manolis Kogevinas, Marc Tischkowitz, Hilary K. Finucane, Hardev Pandha, Rayjean J. Hung, Davor Lessel, Richard S. Houlston, Andrew F. Olshan, André Lopes Carvalho, James D. McKay, Kenneth Offit, Penelope M. Webb, Barry S. Rosenstein, Melinda C. Aldrich, Alice S. Whittemore, Austin Miller, Miguel E. Aguado-Barrera, Amanda E. Toland, Anna Marie Mulligan, Catharine M L West, Susan J. Ramus, Jennifer Stone, David C. Christiani, Clarice R. Weinberg, Olivia Fletcher, Kyriaki Michailidou, Demetrius Albanes, Chu Chen, Jenny L Donovan, Linda E. Kelemen, Carolina Ellberg, Hermann Brenner, Eitan Friedman, Sara Margolin, Jacek Gronwald, Argyrios Ziogas, Elisa V. Bandera, Qin Wang, Christopher I. Amos, Swe-Brca, Douglas F. Easton, Karin Sundfeldt, John L. Hopper, Jong Y. Park, Børge G. Nordestgaard, Johanna Schleutker, Freddie C. Hamdy, Alicja Wolk, Graham Casey, Radka Kaneva, Joe Dennis, Francesmary Modugno, Paolo Radice, Aage Haugen, Ralf Bützow, Barbara Burwinkel, Maria A. Caligo, Paul A. Townsend, Daniel D. Buchanan, Håkan Olsson, Li Li, Elza Khusnutdinova, Karina Dalsgaard Sørensen, Marco Montagna, Patricia A. Ganz, Kirsten B. Moysich, Stephen B. Gruber, Geraldine Cancel-Tassin, Mary Anne Rossing, Mads Thomassen, Manuela Gago-Dominguez, Marjanka K. Schmidt, Jolanta Kupryjanczyk, Melissa C. Southey, Finn Cilius Nielsen, Sara Benlloch, Roger L. Milne, Manuel R. Teixeira, Taymaa May, David V. Conti, Thilo Dörk, Kathleen Claes, Manjeet K. Bolla, Douglas A. Levine, Lorelei A. Mucci, Irene L. Andrulis, Carl Blomqvist, Sara Lindström, Marjorie J. Riggan, Ellen L. Goode, Jenny Lester, Jack A. Taylor, Adam S. Kibel, Jyotsna Batra, Stephen N. Thibodeau, Elinor J. Sawyer, Stefania Boccia, Jacques Simard, Robert J. MacInnis, Fredrik Wiklund, Geoffrey Liu, Robert Winqvist, Robert J. Hamilton, Joan Brunet, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Susan L. Neuhausen, Robert L. Ferris, Georgia Chenevix-Trench, Elizabeth J. van Rensburg, Amanda B. Spurdle, Jeroen R. Huyghe, Stig E. Bojesen, Eric J. Duell, Christopher A. Haiman, Bogdan Pasaniuc, Wilbert H.M. Peters, M. Dawn Teare, Marc T. Goodman, Richa Saxena, Renée T. Fortner, Shanbeh Zienolddiny, Mia M. Gaudet, Stephanie J. Weinstein, Mikael Johansson, Heli Nevanlinna, Nhu D. Le, Rolando Herrero, Peter Kraft, Steven Gallinger, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Erin M. Siegel, Gabriella Cadoni, Weiva Sieh, Esther M. John, Rebecca Sutphen, Kari Stefansson, Loic Le Marchand, David J. Hunter, Alkes L. Price, Judy Garber, Mary B. Daly, Flavio Lejbkowicz, Lambertus A. Kiemeney, Martha L. Slattery, Arto Mannermaa, Christian F. Singer, Daniele Campa, Hans Brunnström, Hongbing Shen, Els Van Nieuwenhuysen, V. Wendy Setiawan, Penella J. Woll, Catherine M. Phelan, Christopher I. Li, Robert L. Nussbaum, Niclas Håkansson, Triantafillos Liloglou, Stella Koutros, Kjell Grankvist, James D. Brenton, Annika Lindblom, Gad Rennert, Karoline Kuchenbaecker, Martin Lacko, Gary E. Goodman, Fredrick R. Schumacher, Henrik Grönberg, Diana Torres, J. Margriet Collée, Rosa B. Barkardottir, Amit Joshi, Trinidad Caldés, Mary Beth Terry, Jenny Chang-Claude, Paul Brennan, Simon A. Gayther, Mark H. Greene, Daniel R. Barnes, Janet L. Stanford, Miriam Dwek, Christiane Maier, Susanne K. Kjaer, Florentia Fostira, Miranda Pring, Noralane M. Lindor, Harvey A. Risch, David G. Huntsman, Kim De Ruyck, Judith A. Clements, Pooja Middha, Alison M. Dunning, Nadine Tung, Sebastian Stintzing, Michael O. Woods, Stephen J. Chanock, Andrew K. Godwin, Kenneth Muir, Eloiza H. Tajara, Silvia Franceschi, Xia Jiang, Li Hsu, Emily White, Peter T. Campbell, Paul A. James, Josef Heinz-Lenz, Ali Amin Al Olama, Victoria L. Stevens, Lovise Maehle, Fotios Loupakis, Peter Devilee, Orland Diez, Kristin K. Zorn, Stephanie A. Bien, Maria Teresa Landi, Mark A. Jenkins, Amanda I. Phipps, Alfons Meindl, Frank Claessens, Mark N. Brook, Kathryn L. Penney, Digna R. Velez Edwards, Montserrat Garcia-Closas, Diether Lambrechts, Zsofia Kote-Jarai, Fergus J. Couch, Duncan Thomas, Kathryn L. Terry, Ute Hamann, Heike Bickeböller, Christopher K. Edlund, Ana Osorio, Younghun Han, Jochen Hampe, Tee Kay-Khaw, Corina Lesseur, Peter A. Fasching, Lesley McGuffog, Eunjung Lee, Tabea Kühl, Andy R Ness, Kamila Czene, Angela Risch, Aocs Mod SQuaD, Jeri Kim, Anna H. Wu, Jacqueline M. Lane, Brenda Diergaarde, Ruth C. Travis, Julie M. Cunningham, Philip Lazarus, Shelley S. Tworoger, Natalia Antonenkova, Emmanouil Saloustros, Wei Zheng, Javier Benitez, Dijana Plaseska-Karanfilska, Mark C. Weissler, Marcia Cruz Correa, Hoda Anton-Culver, Neil E. Caporaso, Cornelia M. Ulrich, Stephanie L. Schmit, Antonis C. Antoniou, Victor Moreno, David E. Neal, Tanja Pejovic, Erich H-Wichmann, Pascal Guénel, Mattias Johansson, Florian Heitz, Beth Y. Karlan, Sonja I. Berndt, Anthony J. Swerdlow, Estrid Høgdall, Hiltrud Brauch, Ulrike Peters, D. Gareth Evans, Celine M. Vachon, Edith Olah, Dale P. Sandler, Lisa F. Newcomb, Michael T. Parsons, Lisa A. Cannon-Albright, Peter J. Hulick, José A. García-Sáenz, Sue A. Ingles, Andrew Berchuck, Peter Hillemanns, Matthew B. Schabath, Polly A. Newcomb, Banu Arun, Xifeng Wu, Darya Prokofyeva, Jan Lubinski, Susanne M. Arnold, Natalia Bogdanova, Drakoulis Yannoukakos, Nawaid Usmani, Kristan J. Aronson, Chul Yun-Hong, Monique J. Roobol, Clinical Genetics, Urology, Læknadeild (HÍ), Faculty of Medicine (UI), Lífvísindasetur (HÍ), Biomedical Center (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Finucane, Hilary K [0000-0003-3864-9828], Schumacher, Fredrick R [0000-0002-3073-7463], Schmit, Stephanie L [0000-0001-5931-1194], Michailidou, Kyriaki [0000-0001-7065-1237], Kuchenbaecker, Karoline B [0000-0001-9726-603X], Dennis, Joe [0000-0003-4591-1214], Huyghe, Jeroen R [0000-0001-6027-9806], Andrulis, Irene L [0000-0002-4226-6435], Arnold, Susanne M [0000-0001-6542-9551], Barnes, Daniel R [0000-0002-3781-7570], Batra, Jyotsna [0000-0003-4646-6247], Bojesen, Stig E [0000-0002-4061-4133], Brauch, Hiltrud [0000-0001-7531-2736], Brenton, James D [0000-0002-5738-6683], Brook, Mark N [0000-0002-8969-2378], Brunet, Joan [0000-0003-1945-3512], Brunnström, Hans [0000-0001-7402-138X], Buchanan, Daniel D [0000-0003-2225-6675], Campbell, Ian [0000-0002-7773-4155], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Chan, Andrew T [0000-0001-7284-6767], Chanock, Stephen J [0000-0002-2324-3393], Claes, Kathleen BM [0000-0003-0841-7372], Cunningham, Julie M [0000-0002-8159-3025], Devilee, Peter [0000-0002-8023-2009], Ellberg, Carolina [0000-0001-7297-0645], Fasching, Peter A [0000-0003-4885-8471], Liloglou, Triantafillos [0000-0003-0460-1404], Fletcher, Olivia [0000-0001-9387-7116], García-Sáenz, José A [0000-0001-6880-0301], Grankvist, Kjell [0000-0003-4289-2097], Greene, Mark H [0000-0003-1852-9239], Gronberg, Henrik [0000-0002-1073-2753], Guénel, Pascal [0000-0002-8359-518X], Hampe, Jochen [0000-0002-2421-6127], Houlston, Richard [0000-0002-5268-0242], Hulick, Peter J [0000-0001-8397-4078], James, Paul [0000-0002-4361-4657], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Lambrechts, Diether [0000-0002-3429-302X], Leslie, Goska [0000-0001-5756-6222], Lessel, Davor [0000-0003-4496-244X], Levine, Douglas A [0000-0003-1038-8232], Miller, Austin [0000-0001-9739-8462], Milne, Roger L [0000-0001-5764-7268], Moreno, Victor [0000-0002-2818-5487], Muir, Kenneth [0000-0001-6429-988X], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Newcomb, Polly A [0000-0001-8786-0043], Nikitina-Zake, Liene [0000-0003-2491-5187], Nordestgaard, Børge G [0000-0002-1954-7220], Olama, Ali Amin Al [0000-0002-7178-3431], Olopade, Olufunmilayo I [0000-0002-9936-1599], Pashayan, Nora [0000-0003-0843-2468], Parsons, Michael T [0000-0003-3242-8477], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Risch, Angela [0000-0002-8026-5505], Roobol, Monique J [0000-0001-6967-1708], Saloustros, Emmanouil [0000-0002-0485-0120], Schabath, Matthew B [0000-0003-3241-3216], Schleutker, Johanna [0000-0002-1863-0305], Schmidt, Marjanka K [0000-0002-2228-429X], Sorensen, Karina Dalsgaard [0000-0002-4902-5490], Stintzing, Sebastian [0000-0002-3297-5801], Stone, Jennifer [0000-0001-5077-0124], Tardon, Adonina [0000-0001-5150-1209], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Aguado-Barrera, Miguel Elías [0000-0002-7822-6726], Webb, Penelope M [0000-0003-0733-5930], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Zheng, Wei [0000-0003-1226-070X], Ziogas, Argyrios [0000-0003-4529-3727], Peters, Ulrike [0000-0001-5666-9318], Eeles, Rosalind A [0000-0002-3698-6241], Brennan, Paul J [0000-0002-0518-8714], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Price, Alkes L [0000-0002-2971-7975], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Jiang X] Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. [Finucane HK] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [Schumacher FR] Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. Seidman Cancer Center, University Hospitals, Cleveland, OH, USA. [Schmit SL] Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. [Han Y] Department of Biomedical Data Science, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. [Diez O] Grup d'Oncogenètica, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain. Hospital Universitari Vall d'Hebron, Barcelona, Spain, Hospital Universitari Vall d'Hebron, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Cancer Research UK (Reino Unido), NIHR - Comprehensive Biomedical Research Centre, Guy ’ s & St. Thomas ’ NHS Foundation Trust, NIHR - Oxford Biomedical Research Centre (Reino Unido), German Cancer Research Center, Consejo Nacional de Ciencia y Tecnología (CONACyT), King College London, National Health and Medical Research Council (Australia), Canadian Institutes of Health Research, The BREast Oncology GAlician Network (BREOGAN, Dietmar-Hopp Foundation, Helmholtz Society and the German Cancer Research Center (DKFZ), Asociación Española Contra el Cáncer, Vall d'Hebron Barcelona Hospital Campus, Clinicum, Department of Oncology, University of Helsinki, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, and HUS Comprehensive Cancer Center

Subjects
Oncology, Male, Lung Neoplasms, Colorectal cancer, Epidemiology, Inheritance Patterns, Genome-wide association study, 02 engineering and technology, Colorectal Neoplasms/diagnosis, Càncer - Aspectes genètics, 0302 clinical medicine, Neoplasm Proteins/genetics, Brjóstakrabbamein, PARTITIONING HERITABILITY, lcsh:Science, Càncer, Cancer genetics, Cancer, Càncer - Estudi de casos, Ovarian Neoplasms, Prostatic Neoplasms/diagnosis, 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Genomics, Publisher Correction, ddc, 3. Good health, Neoplasm Proteins, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Etiologia, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Neoplasias [ENFERMEDADES], ICEP, Erfðarannsóknir, 0210 nano-technology, Genetic Phenomena::Inheritance Patterns [PHENOMENA AND PROCESSES], medicine.medical_specialty, Biolääketieteet - Biomedicine, Science, Lung Neoplasms/diagnosis, European Continental Ancestry Group, Genetic correlation, Article, General Biochemistry, Genetics and Molecular Biology, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Syöpätaudit - Cancers, BREAST-CANCER, Humans, Otros calificadores::Otros calificadores::Otros calificadores::/etnología [Otros calificadores], Polymorphism, GENOME-WIDE ASSOCIATION, solid cancers, heritability, enrichment, Settore MED/42 - IGIENE GENERALE E APPLICATA, ResearchInstitutes_Networks_Beacons/mcrc, Fenómenos Genéticos::Patrón de Herencia [FENÓMENOS Y PROCESOS], ANALYSES IDENTIFY, Biology and Life Sciences, fenómenos genéticos::patrones de herencia [FENÓMENOS Y PROCESOS], medicine.disease, Càncer -- Etiologia, 030104 developmental biology, Case-Control Studies, RISK-FACTORS, lcsh:Q, 0301 basic medicine, Etiology, Medizin, General Physics and Astronomy, técnicas de investigación::métodos epidemiológicos::características de los estudios epidemiológicos::estudios epidemiológicos::estudios de casos y controles [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], head and neck, Prostate cancer, Medicine and Health Sciences, Càncer -- Aspectes genètics, Multidisciplinary, Manchester Cancer Research Centre, Mental Disorders, Codi genètic, Smoking, Single Nucleotide, 021001 nanoscience & nanotechnology, Phenotype, Centre for Surgical Research, Cancer -- Etiology, MENDELIAN RANDOMIZATION, Female, Smoking/ethnology, Colorectal Neoplasms, Mental Disorders/ethnology, Medical Genetics, Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics::Epidemiologic Studies::Case-Control Studies [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], Cancer Etiology, Técnicas de Investigación::Métodos Epidemiológicos::Características de Estudios Epidemiológicos::Estudios Epidemiológicos::Estudios de Casos y Controles [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, All institutes and research themes of the Radboud University Medical Center, Internal medicine, MD Multidisciplinary, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Erfðafræði, Genetic Predisposition to Disease, CELL-TYPES, Lung cancer, Krabbamein, Medicinsk genetik, 030304 developmental biology, Ovarian Neoplasms/diagnosis, Faraldsfræði, Prostatic Neoplasms, Breast Neoplasms/diagnosis, General Chemistry, Heritability, Head and Neck Neoplasms/diagnosis, Neoplasms [DISEASES], Genome-Wide Association Study, 3111 Biomedicine, Ovarian cancer, Other subheadings::Other subheadings::Other subheadings::/ethnology [Other subheadings]
Abstract

Publisher's version (útgefin grein)., Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis., The authors in this manuscript were working on behalf of BCAC, CCFR, CIMBA, CORECT, GECCO, OCAC, PRACTICAL, CRUK, BPC3, CAPS, PEGASUS, TRICL-ILCCO, ABCTB, APCB, BCFR, CONSIT TEAM, EMBRACE, GC-HBOC, GEMO, HEBON, kConFab/AOCS Mod SQuaD, and SWE-BRCA. The breast cancer genome-wide association analyses: BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSR-SIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The Australian Breast Cancer Tissue Bank (ABCTB) is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The ACP study is funded by the Breast Cancer Research Trust, UK. The AHS study is supported by the intramural research program of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFR-NY, BCFR-PA, and BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. BOCS is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). BOCS acknowledges NHS funding to the Royal Marsden/Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The BREast Oncology GAlician Network (BREOGAN) is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CAMA study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462). Sample collection and processing was funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the Canadian Institutes of Health Research. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). COLBCCC is supported by the German Cancer Research Center (DKFZ), Heidelberg, Germany. D.T. was in part supported by a postdoctoral fellowship from the Alexander von Humboldt Foundation. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.C eceives support from the Lon V Smith Foundation (LVS39420). The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, and 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Center (DKFZ). GLACIER was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf-Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and “Practical Research for Innovative Cancer Control (15ck0106177h0001)” from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organizations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014, and 17-44-020498. ICICLE was supported by Breast Cancer Now, CRUK, and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (A.L.F.) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (E.V.O.) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.-T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The KOHBRA study was partially supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute’s Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. L.M.B.C. is supported by the ‘Stichting tegen Kanker’. D.L. is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov” and supported by the German Academic Exchange Program, DAAD. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000”). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839, and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286, and CA177150. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A.-L. Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A.-L. Børresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A.-L. Børresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The Carolina Breast Cancer Study was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, and U01 CA179715), and the North Carolina University Cancer Research Fund. The NGOBCS was supported by Grants-in-Aid for the Third Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, and for Scientific Research on Priority Areas, 17015049 and for Scientific Research on Innovative Areas, 221S0001, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107, and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation, and the special Governmental EVO funds for Oulu University Hospital-based research activities. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956, and Breast Cancer Campaign 2010PR62, 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. SEARCH is funded by Cancer Research UK [C490/A10124, C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute, Thailand. The TNBCC was supported by a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WAABCS study was supported by grants from the National Cancer Institute of the National Institutes of Health (R01 CA89085 and P50 CA125183 and the D43 TW009112 grant), Susan G. Komen (SAC110026), the Dr. Ralph and Marian Falk Medical Research Trust, and the Avon Foundation for Women. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. D.G.E. is supported by the all Manchester NIHR Biomedical research center Manchester (IS-BRC-1215-20007). HUNBOCS, Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grant KTIA-OTKA CK-80745, NKFI_OTKA K-112228. C.I. received support from the Nontherapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI P30-CA-51008) and the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research. K.M. is supported by CRUK C18281/A19169. City of Hope Clinical Cancer Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J Weitzel) from the National Cancer Institute and the office of the Directory, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The colorectal cancer genome-wide association analyses: Colorectal Transdisciplinary Study (CORECT): The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CORECT Consortium, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the CORECT Consortium. We are incredibly grateful for the contributions of Dr. Brian Henderson and Dr. Roger Green over the course of this study and acknowledge them in memoriam. We are also grateful for support from Daniel and Maryann Fong. ColoCare: we thank the many investigators and staff who made this research possible in ColoCare Seattle and ColoCare Heidelberg. ColoCare was initiated and developed at the Fred Hutchinson Cancer Research Center by Drs. Ulrich and Grady. CCFR: the Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and financial support from the U.S. National Cancer Institute, without which this important registry would not exist. Galeon: GALEON wishes to thank the Department of Surgery of University Hospital of Santiago (CHUS), Sara Miranda Ponte, Carmen M Redondo, and the staff of the Department of Pathology and Biobank of CHUS, Instituto de Investigación Sanitaria de Santiago (IDIS), Instituto de Investigación Sanitaria Galicia Sur (IISGS), SERGAS, Vigo, Spain, and Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Salud Carlos III, Spain. MCCS: this study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited participants and continue to work on follow-up. We would also like to express our gratitude to the many thousands of Melbourne residents who took part in the study and provided blood samples. SEARCH: We acknowledge the contributions of Mitul Shah, Val Rhenius, Sue Irvine, Craig Luccarini, Patricia Harrington, Don Conroy, Rebecca Mayes, and Caroline Baynes. The Swedish low-risk colorectal cancer study: we thank Berith Wejderot and the Swedish low-risk colorectal cancer study group. Genetics & Epidemiology of Colorectal Cancer Consortium (GECCO): we thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK: we are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik, and Ursula Eilber for excellent technical assistance. HPFS, NHS and PHS: we acknowledge Patrice Soule and Hardeep Ranu of the Dana-Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo, and Lixue Zhu who assisted in programming for NHS and HPFS and Haiyan Zhang who assisted in programming for the PHS. We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., W.Y. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. We assume full responsibility for analyses and interpretation of these data. PLCO: we thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services Inc., Ms. Barbara O’Brien and staff, Westat Inc. and Drs. Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions for making this study possible. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI. PMH: we thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short20List.pdf. CORECT: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; and R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). The ATBC Study was supported by the US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. The Cancer Prevention Study-II Nutrition Cohort is funded by the American Cancer Society. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184, U01 CA206110, 2P30CA015704-40 (Gilliland)), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): funding for GECCO was provided by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045, and U01 CA164930). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S.G.). The Colon CFR participant recruitment and collection of data and biospecimens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number UM1 CA167551) and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806), Additional support for case ascertainment was provided from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai’i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137, and Contract No. HHSN26120100037C, and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California, and the following state cancer registries: A.Z., C.O., M.N., N.C., N.H., and by the Victoria Cancer Registry and Ontario Cancer Registry. ESTHER/VERDI was supported by grants from the Baden–Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MSKCC: the work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). SEARCH: Cancer Research UK (C490/A16561). The Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Catalan Government DURSI (grant 2014SGR647), and Junta de Castilla y León (grant LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: the study was supported by grants from the Swedish research council; K2015-55 × -22674-01-4, K2008-55 × -20157-03-3, K2006-72 × -20157-01-2 and the Stockholm County Council (ALF project). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I (to K.D.), through grant 101HG007491-01 (to C.I.A.). The Norris Cotton Cancer Center - P30CA023108, The Quantitative Biology Research Institute - P20GM103534, and the Coordinating Center for Screen Detected Lesions - U01CA196386 also supported efforts of C.I.A. This work was also supported by the National Cancer Institute (grant numbers U01 CA1817700, R01 CA144040). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (grant number R01 CA060987). DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). DALS: National Institutes of Health (grant number R01 CA048998 to M.L.S). HPFS is supported by National Institutes of Health (grant numbers P01 CA055075, UM1 CA167552, R01 137178, and P50 CA127003), NHS by the National Institutes of Health (grant numbers UM1 CA186107, R01 CA137178, P01 CA087969, and P50 CA127003), NHSII by the National Institutes of Health (grant numbers R01 050385CA and UM1 CA176726), and PHS by the National Institutes of Health (grant number R01 CA042182). MEC: National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, and R01 CA063464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant number U01 CA074783); see Colon CFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. and B.W.Z. are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, 23 and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (grant number R01 CA076366). VITAL: National Institutes of Health (grant number K05-CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The head and neck cancer genome-wide association analyses: The study was supported by NIH/NCI: P50 CA097190, and P30 CA047904, Canadian Cancer Society Research Institute (no. 020214) and Cancer Care Ontario Research Chair to R.H. The Princess Margaret Hospital Head and Neck Cancer Translational Research Program is funded by the Wharton family, Joe’s Team, Gordon Tozer, Bruce Galloway and the Elia family. Geoffrey Liu was supported by the Posluns Family Fund and the Lusi Wong Family Fund at the Princess Margaret Foundation, and the Alan B. Brown Chair in Molecular Genomics. This publication presents data from Head and Neck 5000 (H&N5000). H&N5000 was a component of independent research funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) in H&N5000 serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). National Cancer Institute (R01-CA90731); National Institute of Environmental Health Sciences (P30ES10126). The authors thank all the members of the GENCAPO team/The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). CPS-II recruitment and maintenance is supported with intramural research funding from the American Cancer Society. Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1 × 01HG007780-0. The University of Pittsburgh head and neck cancer case-control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19-CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission’s 5th Framework Program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to S.B., and Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). We thank Leticia Fernandez, Instituto Nacional de Oncologia y Radiobiologia, La Habana, Cuba and Sergio and Rosalina Koifman, for their efforts with the IARC Latin America study São Paulo center. The IARC Central Europe study was supported by European Commission’s INCO-COPERNICUS Program (IC15- CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The lung cancer genome-wide association analyses: Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by (U19-CA148127, CA148127S1, U19CA203654, and Cancer Prevention Research Institute of Texas RR170048). The ILCCO data harmonization is supported by Cancer Care Ontario Research Chair of Population Studies to R. H. and Lunenfeld-Tanenbaum Research Institute, Sinai Health System. The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989-01A1(PI Doherty). The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, CA074386. The Multi-ethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464, and CA148127. The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), the National Key Basic Research Program Grant (2011CB503805), the Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study (SCS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The Singapore Chinese Health Study (SCHS) was supported by National Institutes of Health R01 CA144034 (PI: Yuan) and UM1 CA182876 (PI: Yuan). The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The Vanderbilt Lung Cancer Study—BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH. Dr. Aldrich was supported by NIH/National Cancer Institute K07CA172294 (PI: Aldrich) and Dr. Bush was supported by NHGRI/NIH U01HG004798 (PI: Crawford). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The M.D. Anderson Cancer Center study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568) (to X.W.), Cancer Prevention & Research Institute of Texas (RP130502) (to X.W.), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The deCODE study of smoking and nicotine dependence was funded in part by a grant from NIDA (R01- DA017932). The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer—field study. Genetic sharing analysis was funded by NIH grant CA194393. The research undertaken by M.D.T., L.V.W., and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The work to assemble the FTND GWAS meta-analysis was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) grant number R01 DA035825 (Principal Investigator [PI]: DBH). The study populations included COGEND (dbGaP phs000092.v1.p1 and phs000404.v1.p1), COPDGene (dbGaP phs000179.v3.p2), deCODE Genetics, EAGLE (dbGaP phs000093.vs.p2), and SAGE. dbGaP phs000092.v1.p1). See Hancock et al. Transl Psychiatry 2015 (PMCID: PMC4930126) for the full listing of funding sources and other acknowledgments. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT)study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. The ovarian cancer genome-wide association analysis: The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.), and R01-CA058598 (M.T.G.); Canadian Institutes of Health Research (MOP-86727 (L.E.K.) and the Ovarian Cancer Research Fund (A.B.). The COGS project was funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175) and through a grant from the U.S. National Institutes of Health (R01-CA122443 (E.L.G)). Funding for individual studies: AAS: National Institutes of Health (RO1-CA142081); AOV: The Canadian Institutes for Health Research (MOP-86727); AUS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BEL: National Kankerplan; BGS: Breast Cancer Now, Institute of Cancer Research; BVU: Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; CHA: Innovative Research Team in University (PCSIRT) in China (IRT1076); CNI: Instituto de Salud Carlos III (PI12/01319); Ministerio de Economía y Competitividad (SAF2012); COE: Department of Defense (W81XWH-11-2-0131); CON: National Institutes of Health (R01-CA063678, R01-CA074850; and R01-CA080742); DKE: Ovarian Cancer Research Fund; DOV: National Institutes of Health R01-CA112523 and R01-CA87538; EMC: Dutch Cancer Society (EMC 2014-6699); EPC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom); GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); GRC: This research has been co-financed by the European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund; GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056; HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424, and N01-PC-67001); HJO: Intramural funding; Rudolf-Bartling Foundation; HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, P50-CA159981 MO1-RR000056 R01-CA126841); HUO: Intramural funding; Rudolf-Bartling Foundation; JGO: JSPS KAKENHI grant; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; KRA: This study (Ko-EVE) was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 0920010); LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; LUN: ERC-2011-AdG 294576-risk factors cancer, Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation; MAC: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles; MAL: Funding for this study was provided by research grant R01- CA61107 from the National Cancer Institute, Bethesda, MD, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project; MAS: Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, and P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: Cancer Council Victoria, National Health and Medical Research Council of Australia (NHMRC) grants number 209057, 251533, 396414, and 504715; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01-CA67262, UM1 CA176726; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey; If Sara Olson and/or Irene Orlow is a co-author, please add NCI CCSG award (P30-CA008748) to the funding sources; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women’s Club; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; PLC: Intramural Research Program of the National Cancer Institute; POC: Pomeranian Medical University; POL: Intramural Research Program of the National Cancer Institute; PVD: Canadian Cancer Society and Cancer Research Society GRePEC Program; RBH: National Health and Medical Research Council of Australia; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50-CA159981, R01-CA126841); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: NIH, National Institute of Environmental Health Sciences, Z01-ES044005 and Z01-ES049033; SMC: The bbSwedish Research Council-SIMPLER infrastructure; the Swedish Cancer Foundation; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589); STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and VårKampMotCancer foundation; SWH: NIH (NCI) grant R37-CA070867; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01-CA063678 and R01 CA063682; UCI: NIH R01-CA058860 and the Lon V Smith Foundation grant LVS39420; UHN: Princess Margaret Cancer Centre Foundation-Bridge for the Cure; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; UKR: Cancer Research UK (C490/A6187), UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200); VAN: BC Cancer Foundation, VGH & UBC Hospital Foundation; VTL: NIH K05-CA154337; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16; WOC: National Science Centren (N N301 5645 40). The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academia Reserve. The prostate cancer genome-wide association analyses: we pay tribute to Brian Henderson, who was a driving force behind the OncoArray project, for his vision and leadership, and who sadly passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. The ELLIPSE/PRACTICAL (http//:practical.icr.ac.uk) prostate cancer consortium and his collaborating partners were supported by multiple funding mechanisms enabling this current work. ELLIPSE/PRACTICAL Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA148537 for ELucidating Loci Involved in Prostate Cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytical support was provided by NIH NCI U01 CA188392 (F.R.S.). Funding for the iCOGS infrastructure came from the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112; the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, C5047/A21332 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA148537-01 (the GAME-ON initiative). We also thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for their support. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). CAPS GWAS study was supported by the Swedish Cancer Foundation (grant no 09-0677, 11-484, 12-823), the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant no K2010-70 × -20430-04-3, 2014-2269). The Hannover Prostate Cancer Study was supported by the Lower Saxonian Cancer Society. PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. RAPPER was supported by the NIHR Manchester Biomedical Research Center, Cancer Research UK (C147/A25254, C1094/A18504) and the EU’s 7th Framework Programme Grant/Agreement no 60186. Overall: this research has been conducted using the UK Biobank Resource (application number 16549). NHS is supported by UM1 CA186107 (NHS cohort infrastructure grant), P01 CA87969, and R01 CA49449. NHSII is supported by UM1 CA176726 (NHSII cohort infrastructure grant), and R01-CA67262. A.L.K. is supported by R01 MH107649. We would like to thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

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2019

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