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1. Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

Author

Haas CB, Chen H, Harrison T, Fan S, Gago-Dominguez M, Castelao JE, Bolla MK, Wang Q, Dennis J, Michailidou K, Dunning AM, Easton DF, Antoniou AC, Hall P, Czene K, Andrulis IL, Mulligan AM, Milne RL, Fasching PA, Haeberle L, Garcia-Closas M, Ahearn T, Gierach GL, Haiman C, Maskarinec G, Couch FJ, Olson JE, John EM, Chenevix-Trench G, Berrington de Gonzalez A, Jones M, Stone J, Murphy R, Aronson KJ, Wernli KJ, Hsu L, Vachon C, Tamimi RM, and Lindström S

Subjects
Humans, Female, Sex Hormone-Binding Globulin analysis, Sex Hormone-Binding Globulin metabolism, Sex Hormone-Binding Globulin genetics, Middle Aged, Polymorphism, Single Nucleotide, Mammography, Estradiol blood, Testosterone blood, Phenotype, Breast Density, Mendelian Randomization Analysis, Body Mass Index, Breast Neoplasms genetics, Breast Neoplasms blood, Breast Neoplasms diagnostic imaging, Genome-Wide Association Study, Gonadal Steroid Hormones blood
Abstract

Purpose: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR)., Methods: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status., Results: Genetically predicted BMI was positively associated with non-dense area (IVW: β = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10 -63 ) and inversely associated with dense area (IVW: β = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10 -7 ). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (β = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (β =  - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches., Conclusion: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2024
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2. Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

Author

Jia G, Ping J, Shu X, Yang Y, Cai Q, Kweon SS, Choi JY, Kubo M, Park SK, Bolla MK, Dennis J, Wang Q, Guo X, Li B, Tao R, Aronson KJ, Chan TL, Gao YT, Hartman M, Ho WK, Ito H, Iwasaki M, Iwata H, John EM, Kasuga Y, Kim MK, Kurian AW, Kwong A, Li J, Lophatananon A, Low SK, Mariapun S, Matsuda K, Matsuo K, Muir K, Noh DY, Park B, Park MH, Shen CY, Shin MH, Spinelli JJ, Takahashi A, Tseng C, Tsugane S, Wu AH, Yamaji T, Zheng Y, Dunning AM, Pharoah PDP, Teo SH, Kang D, Easton DF, Simard J, Shu XO, Long J, and Zheng W

Subjects
Female, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Transcriptome genetics, Case-Control Studies, Genome-Wide Association Study, Breast Neoplasms genetics
Abstract

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10 -8 and a Bonferroni-corrected p < 4.6 × 10 -6 , respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2022
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3. Rare germline copy number variants (CNVs) and breast cancer risk.

Author

Dennis J, Tyrer JP, Walker LC, Michailidou K, Dorling L, Bolla MK, Wang Q, Ahearn TU, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Freeman LEB, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Brenner H, Castelao JE, Chang-Claude J, Chenevix-Trench G, Clarke CL, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dörk T, Dossus L, Eliassen AH, Eriksson M, Evans DG, Fasching PA, Figueroa J, Fletcher O, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, García-Closas M, Giles GG, González-Neira A, Guénel P, Hahnen E, Haiman CA, Hall P, Hollestelle A, Hoppe R, Hopper JL, Howell A, Jager A, Jakubowska A, John EM, Johnson N, Jones ME, Jung A, Kaaks R, Keeman R, Khusnutdinova E, Kitahara CM, Ko YD, Kosma VM, Koutros S, Kraft P, Kristensen VN, Kubelka-Sabit K, Kurian AW, Lacey JV, Lambrechts D, Larson NL, Linet M, Ogrodniczak A, Mannermaa A, Manoukian S, Margolin S, Mavroudis D, Milne RL, Muranen TA, Murphy RA, Nevanlinna H, Olson JE, Olsson H, Park-Simon TW, Perou CM, Peterlongo P, Plaseska-Karanfilska D, Pylkäs K, Rennert G, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Shibli R, Smeets A, Soucy P, Southey MC, Swerdlow AJ, Tamimi RM, Taylor JA, Teras LR, Terry MB, Tomlinson I, Troester MA, Truong T, Vachon CM, Wendt C, Winqvist R, Wolk A, Yang XR, Zheng W, Ziogas A, Simard J, Dunning AM, Pharoah PDP, and Easton DF

Subjects
Case-Control Studies, Female, Humans, Risk Factors, Breast Neoplasms genetics, DNA Copy Number Variations, Genome, Human, Genome-Wide Association Study, Germ Cells
Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance., (© 2022. The Author(s).)

Published
2022
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4. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author

Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL, Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hulick PJ, Hunter DJ, Imyanitov EN, Jager A, Jakubowska A, James PA, Jensen UB, John EM, Jones ME, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khusnutdinova E, Kiiski JI, Ko YD, Kosma VM, Kraft P, Kurian AW, Laitman Y, Lambrechts D, Le Marchand L, Lester J, Lesueur F, Lindstrom T, Lopez-Fernández A, Loud JT, Luccarini C, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Mebirouk N, Meindl A, Miller A, Milne RL, Montagna M, Nathanson KL, Neuhausen SL, Nevanlinna H, Nielsen FC, O'Brien KM, Olopade OI, Olson JE, Olsson H, Osorio A, Ottini L, Park-Simon TW, Parsons MT, Pedersen IS, Peshkin B, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Polley EC, Poppe B, Presneau N, Pujana MA, Punie K, Radice P, Rantala J, Rashid MU, Rennert G, Rennert HS, Robson M, Romero A, Rossing M, Saloustros E, Sandler DP, Santella R, Scheuner MT, Schmidt MK, Schmidt G, Scott C, Sharma P, Soucy P, Southey MC, Spinelli JJ, Steinsnyder Z, Stone J, Stoppa-Lyonnet D, Swerdlow A, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Teulé A, Thull DL, Tischkowitz M, Toland AE, Torres D, Trainer AH, Truong T, Tung N, Vachon CM, Vega A, Vijai J, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wolk A, Yadav S, Yang XR, Yannoukakos D, Zheng W, Ziogas A, Zorn KK, Park SK, Thomassen M, Offit K, Schmutzler RK, Couch FJ, Simard J, Chenevix-Trench G, Easton DF, Andrieu N, and Antoniou AC

Subjects
Adult, Alleles, Female, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Mutation, Quantitative Trait Loci genetics, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10 -8 , at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

Published
2021
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5. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Author

Feng H, Gusev A, Pasaniuc B, Wu L, Long J, Abu-Full Z, Aittomäki K, Andrulis IL, Anton-Culver H, Antoniou AC, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barrowdale D, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Białkowska K, Blanco A, Blomqvist C, Boeckx B, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brüning T, Burwinkel B, Cai Q, Caldés T, Caligo MA, Campbell I, Canisius S, Campa D, Carter BD, Carter J, Castelao JE, Chang-Claude J, Chanock SJ, Christiansen H, Chung WK, Claes KBM, Clarke CL, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, De Leeneer K, Dennis J, Devilee P, Diez O, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Ejlertsen B, Ellberg C, Engel C, Eriksson M, Fasching PA, Fletcher O, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gabrielson M, Ganz PA, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hamann U, Hake C, He W, Heyworth J, Hogervorst FBL, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Huang G, Hulick PJ, Humphreys K, Imyanitov EN, Isaacs C, Jakimovska M, Jakubowska A, James P, Janavicius R, Jankowitz RC, John EM, Johnson N, Joseph V, Jung A, Karlan BY, Khusnutdinova E, Kiiski JI, Konstantopoulou I, Kristensen VN, Laitman Y, Lambrechts D, Lazaro C, Leroux D, Leslie G, Lester J, Lesueur F, Lindor N, Lindström S, Lo WY, Loud JT, Lubiński J, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martens JWM, Martinez ME, Matricardi L, Maurer T, Mavroudis D, McGuffog L, Meindl A, Menon U, Michailidou K, Kapoor PM, Miller A, Montagna M, Moreno F, Moserle L, Mulligan AM, Muranen TA, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Nielsen FC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Olsson H, Osorio A, Papp J, Park-Simon TW, Parsons MT, Pedersen IS, Peixoto A, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Plaseska-Karanfilska D, Poppe B, Pradhan N, Prajzendanc K, Presneau N, Punie K, Pylkäs K, Radice P, Rantala J, Rashid MU, Rennert G, Risch HA, Robson M, Romero A, Saloustros E, Sandler DP, Santos C, Sawyer EJ, Schmidt MK, Schmidt DF, Schmutzler RK, Schoemaker MJ, Scott RJ, Sharma P, Shu XO, Simard J, Singer CF, Skytte AB, Soucy P, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Swerdlow AJ, Tapper WJ, Taylor JA, Teixeira MR, Terry MB, Teulé A, Thomassen M, Thöne K, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Torres D, Truong T, Tung N, Vachon CM, van Asperen CJ, van den Ouweland AMW, van Rensburg EJ, Vega A, Viel A, Vieiro-Balo P, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Winqvist R, Yang XR, Yannoukakos D, Ziogas A, Milne RL, Easton DF, Chenevix-Trench G, Zheng W, Kraft P, and Jiang X

Subjects
Breast Neoplasms metabolism, Estrogens metabolism, Female, Genetic Predisposition to Disease, Genomics, Humans, Risk Assessment, Transcriptome, Vesicular Transport Proteins genetics, Breast Neoplasms genetics, Genome-Wide Association Study, Receptors, Estrogen metabolism
Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer., (© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.)

Published
2020
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6. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author

Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, Jiang X, O'Mara TA, Zhao N, Bolla MK, Dunning AM, Dennis J, Wang Q, Ful ZA, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Arun BK, Auer PL, Azzollini J, Barrowdale D, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bialkowska K, Blanco A, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Bondavalli D, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brucker SY, Brüning T, Burwinkel B, Buys SS, Byers H, Caldés T, Caligo MA, Calvello M, Campa D, Castelao JE, Chang-Claude J, Chanock SJ, Christiaens M, Christiansen H, Chung WK, Claes KBM, Clarke CL, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Diez O, Domchek SM, Dörk T, Dwek M, Eccles DM, Ekici AB, Evans DG, Fasching PA, Figueroa J, Foretova L, Fostira F, Friedman E, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Häberle L, Hahnen E, Haiman CA, Hake CR, Hall P, Hamann U, Harkness EF, Heemskerk-Gerritsen BAM, Hillemanns P, Hogervorst FBL, Holleczek B, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huebner H, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Jager A, Jakimovska M, Jakubowska A, James P, Janavicius R, Janni W, John EM, Jones ME, Jung A, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khan S, Khusnutdinova E, Kitahara CM, Ko YD, Konstantopoulou I, Koppert LB, Koutros S, Kristensen VN, Laenkholm AV, Lambrechts D, Larsson SC, Laurent-Puig P, Lazaro C, Lazarova E, Lejbkowicz F, Leslie G, Lesueur F, Lindblom A, Lissowska J, Lo WY, Loud JT, Lubinski J, Lukomska A, MacInnis RJ, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matricardi L, McGuffog L, McLean C, Mebirouk N, Meindl A, Menon U, Miller A, Mingazheva E, Montagna M, Mulligan AM, Mulot C, Muranen TA, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen FC, Nikitina-Zake L, Nodora J, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Papi L, Papp J, Park-Simon TW, Parsons MT, Peissel B, Peixoto A, Peshkin B, Peterlongo P, Peto J, Phillips KA, Piedmonte M, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Prokofyeva D, Rack B, Radice P, Ramus SJ, Rantala J, Rashid MU, Rennert G, Rennert HS, Risch HA, Romero A, Rookus MA, Rübner M, Rüdiger T, Saloustros E, Sampson S, Sandler DP, Sawyer EJ, Scheuner MT, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Senter L, Sharma P, Sherman ME, Shu XO, Singer CF, Smichkoska S, Soucy P, Southey MC, Spinelli JJ, Stone J, Stoppa-Lyonnet D, Swerdlow AJ, Szabo CI, Tamimi RM, Tapper WJ, Taylor JA, Teixeira MR, Terry M, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Troester MA, Truong T, Tung N, Untch M, Vachon CM, van den Ouweland AMW, van der Kolk LE, van Veen EM, vanRensburg EJ, Vega A, Wappenschmidt B, Weinberg CR, Weitzel JN, Wildiers H, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zheng W, Zorn KK, Milne RL, Kraft P, Simard J, Pharoah PDP, Michailidou K, Antoniou AC, Schmidt MK, Chenevix-Trench G, Easton DF, Chatterjee N, and García-Closas M

Subjects
BRCA1 Protein genetics, Breast Neoplasms pathology, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Mutation, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Breast Neoplasms genetics, Genome-Wide Association Study
Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype 1-3 . To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10 -8 ), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Published
2020
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7. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author

Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, Pooley KA, Dennis J, Michailidou K, Turman C, Soucy P, Lemaçon A, Lush M, Tyrer JP, Ghoussaini M, Moradi Marjaneh M, Jiang X, Agata S, Aittomäki K, Alonso MR, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Aronson KJ, Arun BK, Auber B, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Beeghly-Fadiel A, Benitez J, Bermisheva M, Białkowska K, Blanco AM, Blomqvist C, Blot W, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Bosse K, Brauch H, Brenner H, Briceno I, Brock IW, Brooks-Wilson A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldés T, Caligo MA, Camp NJ, Campbell I, Canzian F, Carroll JS, Carter BD, Castelao JE, Chiquette J, Christiansen H, Chung WK, Claes KBM, Clarke CL, Collée JM, Cornelissen S, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Domchek SM, Dörk T, Dos-Santos-Silva I, Droit A, Dubois S, Dumont M, Duran M, Durcan L, Dwek M, Eccles DM, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Floris G, Flyger H, Foretova L, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gago-Dominguez M, Gambino G, Ganz PA, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Tibiletti MG, Greene MH, Grip M, Gronwald J, Grundy A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hartikainen JM, Hartman M, He W, Healey CS, Heemskerk-Gerritsen BAM, Heyworth J, Hillemanns P, Hogervorst FBL, Hollestelle A, Hooning MJ, Hopper JL, Howell A, Huang G, Hulick PJ, Imyanitov EN, Isaacs C, Iwasaki M, Jager A, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kang D, Kapoor PM, Karlan BY, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Kirk J, Kitahara CM, Ko YD, Konstantopoulou I, Kosma VM, Koutros S, Kubelka-Sabit K, Kwong A, Kyriacou K, Laitman Y, Lambrechts D, Lee E, Leslie G, Lester J, Lesueur F, Lindblom A, Lo WY, Long J, Lophatananon A, Loud JT, Lubiński J, MacInnis RJ, Maishman T, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matsuo K, Maurer T, Mavroudis D, Mayes R, McGuffog L, McLean C, Mebirouk N, Meindl A, Miller A, Miller N, Montagna M, Moreno F, Muir K, Mulligan AM, Muñoz-Garzon VM, Muranen TA, Narod SA, Nassir R, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nikitina-Zake L, Norman A, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Osorio A, Pankratz VS, Papp J, Park SK, Park-Simon TW, Parsons MT, Paul J, Pedersen IS, Peissel B, Peshkin B, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Prokofyeva D, Pujana MA, Pylkäs K, Radice P, Ramus SJ, Rantala J, Rau-Murthy R, Rennert G, Risch HA, Robson M, Romero A, Rossing M, Saloustros E, Sánchez-Herrero E, Sandler DP, Santamariña M, Saunders C, Sawyer EJ, Scheuner MT, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Scott C, Scott RJ, Senter L, Seynaeve CM, Shah M, Sharma P, Shen CY, Shu XO, Singer CF, Slavin TP, Smichkoska S, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Stoppa-Lyonnet D, Sutter C, Swerdlow AJ, Tamimi RM, Tan YY, Tapper WJ, Taylor JA, Teixeira MR, Tengström M, Teo SH, Terry MB, Teulé A, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Torres-Mejía G, Troester MA, Truong T, Tung N, Tzardi M, Ulmer HU, Vachon CM, van Asperen CJ, van der Kolk LE, van Rensburg EJ, Vega A, Viel A, Vijai J, Vogel MJ, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wildiers H, Winqvist R, Wolk A, Wu AH, Yannoukakos D, Zhang Y, Zheng W, Hunter D, Pharoah PDP, Chang-Claude J, García-Closas M, Schmidt MK, Milne RL, Kristensen VN, French JD, Edwards SL, Antoniou AC, Chenevix-Trench G, Simard J, Easton DF, Kraft P, and Dunning AM

Subjects
Bayes Theorem, Female, Humans, Linkage Disequilibrium, Regulatory Sequences, Nucleic Acid, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Chromosome Mapping methods, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Published
2020
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8. Association analysis identifies 65 new breast cancer risk loci.

Author

Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, Lemaçon A, Soucy P, Glubb D, Rostamianfar A, Bolla MK, Wang Q, Tyrer J, Dicks E, Lee A, Wang Z, Allen J, Keeman R, Eilber U, French JD, Qing Chen X, Fachal L, McCue K, McCart Reed AE, Ghoussaini M, Carroll JS, Jiang X, Finucane H, Adams M, Adank MA, Ahsan H, Aittomäki K, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Arun B, Auer PL, Bacot F, Barrdahl M, Baynes C, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Brinton L, Broberg P, Brock IW, Broeks A, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Butterbach K, Cai Q, Cai H, Caldés T, Canzian F, Carracedo A, Carter BD, Castelao JE, Chan TL, David Cheng TY, Seng Chia K, Choi JY, Christiansen H, Clarke CL, Collée M, Conroy DM, Cordina-Duverger E, Cornelissen S, Cox DG, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Elvira M, Engel C, Eriksson M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gaborieau V, Gabrielson M, Gago-Dominguez M, Gao YT, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hamel N, Hankinson S, Harrington P, Hart SN, Hartikainen JM, Hartman M, Hein A, Heyworth J, Hicks B, Hillemanns P, Ho DN, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Hou MF, Hsiung CN, Huang G, Humphreys K, Ishiguro J, Ito H, Iwasaki M, Iwata H, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kasuga Y, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Kosma VM, Kristensen VN, Krüger U, Kwong A, Lambrechts D, Le Marchand L, Lee E, Lee MH, Lee JW, Neng Lee C, Lejbkowicz F, Li J, Lilyquist J, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Lophatananon A, Lubinski J, Luccarini C, Lux MP, Ma ESK, MacInnis RJ, Maishman T, Makalic E, Malone KE, Kostovska IM, Mannermaa A, Manoukian S, Manson JE, Margolin S, Mariapun S, Martinez ME, Matsuo K, Mavroudis D, McKay J, McLean C, Meijers-Heijboer H, Meindl A, Menéndez P, Menon U, Meyer J, Miao H, Miller N, Taib NAM, Muir K, Mulligan AM, Mulot C, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Noh DY, Nordestgaard BG, Norman A, Olopade OI, Olson JE, Olsson H, Olswold C, Orr N, Pankratz VS, Park SK, Park-Simon TW, Lloyd R, Perez JIA, Peterlongo P, Peto J, Phillips KA, Pinchev M, Plaseska-Karanfilska D, Prentice R, Presneau N, Prokofyeva D, Pugh E, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Ruddy KJ, Rüdiger T, Rudolph A, Ruebner M, Rutgers EJT, Saloustros E, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Scott RJ, Scott C, Seal S, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng G, Sherman ME, Shrubsole MJ, Shu XO, Smeets A, Sohn C, Southey MC, Spinelli JJ, Stegmaier C, Stewart-Brown S, Stone J, Stram DO, Surowy H, Swerdlow A, Tamimi R, Taylor JA, Tengström M, Teo SH, Beth Terry M, Tessier DC, Thanasitthichai S, Thöne K, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Truong T, Tseng CC, Tsugane S, Ulmer HU, Ursin G, Untch M, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van der Kolk L, van der Luijt RB, Vincent D, Vollenweider J, Waisfisz Q, Wang-Gohrke S, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yamaji T, Yang XR, Har Yip C, Yoo KY, Yu JC, Zheng W, Zheng Y, Zhu B, Ziogas A, Ziv E, Lakhani SR, Antoniou AC, Droit A, Andrulis IL, Amos CI, Couch FJ, Pharoah PDP, Chang-Claude J, Hall P, Hunter DJ, Milne RL, García-Closas M, Schmidt MK, Chanock SJ, Dunning AM, Edwards SL, Bader GD, Chenevix-Trench G, Simard J, Kraft P, and Easton DF

Subjects
Asia ethnology, Asian People genetics, Binding Sites genetics, Breast Neoplasms diagnosis, Computer Simulation, Europe ethnology, Female, Humans, Multifactorial Inheritance genetics, Polymorphism, Single Nucleotide genetics, Regulatory Sequences, Nucleic Acid, Risk Assessment, Transcription Factors metabolism, White People genetics, Breast Neoplasms genetics, Genetic Loci, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Published
2017
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9. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author

Middha, Pooja, Wang, Xiaoliang, Behrens, Sabine, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baert, Thaïs, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Benitez, Javier, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dossus, Laure, Dugué, Pierre-Antoine, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine D, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Giles, Graham G, González-Neira, Anna, Grassmann, Felix, Grundy, Anne, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan E, Harkness, Elaine F, Holleczek, Bernd, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Ingvar, Christian, Isaksson, Karolin, Jernström, Helena, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Larsson, Susanna, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Shuai, Linet, Martha, Lissowska, Jolanta, Martinez, Maria Elena, Maurer, Tabea, Mulligan, Anna Marie, Mulot, Claire, Murphy, Rachel A, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, O’Brien, Katie M, Olson, Janet E, Patel, Alpa V, Prentice, Ross, Rees-Punia, Erika, Rennert, Gad, Rhenius, Valerie, Ruddy, Kathryn J, and Sandler, Dale P

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer Genomics, Human Genome, Estrogen, Cancer, Women's Health, Genetics, Prevention, Aging, Breast Cancer, 2.1 Biological and endogenous factors, Adult, Female, Humans, Gene-Environment Interaction, Genetic Predisposition to Disease, Breast Neoplasms, Bayes Theorem, Genome-Wide Association Study, Risk Factors, Polymorphism, Single Nucleotide, Case-Control Studies, Breast cancer, Gene-environment interactions, Genetic epidemiology, European ancestry, CTS Consortium, ABCTB Investigators, kConFab Investigators, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundGenome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.MethodsAnalyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.ResultsAssuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Published
2023

10. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author

Mueller, Stefanie H, Lai, Alvina G, Valkovskaya, Maria, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Abu-Ful, Zomoruda, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baert, Thais, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brenner, Hermann, Brucker, Sara Y, Buys, Saundra S, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Chung, Wendy K, Colonna, Sarah V, Cornelissen, Sten, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Yu-Tang, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Gentry-Maharaj, Aleksandra, Grassmann, Felix, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Harkness, Elaine F, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, Hein, Alexander, Ho, Weang-Kee, Hooning, Maartje J, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Khusnutdinova, Elza K, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, Lacey, James V, Lambrechts, Diether, and Le Marchand, Loic

Subjects
Breast Cancer, Genetics, Clinical Research, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Black People, Genetic Testing, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Formins, Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, NBCS Collaborators, CTS Consortium, ABCTB Investigators, Clinical Sciences
Abstract

BackgroundLow-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.MethodsWe evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.ResultsIn European ancestry samples, 14 genes were significantly associated (q

Published
2023

11. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author

Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Krüger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, and McLean, Catriona

Subjects
Human Genome, Cancer, Genetics, Clinical Research, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Breast Neoplasms, Female, Genome-Wide Association Study, Humans, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Risk, Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, NBCS Collaborators, ABCTB Investigators, kConFab/AOCS Investigators, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Published
2022

12. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author

Park, Hanla A, Neumeyer, Sonja, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baten, Adinda, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brucker, Sara Y, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fritschi, Lin, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Grip, Mervi, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny, Harkness, Elaine F, Hart, Steven N, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hopper, John L, Hunter, David J, Jager, Agnes, Jakubowska, Anna, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Kurian, Allison W, Lacey, James, Lambrechts, Diether, Le Marchand, Loic, Lo, Wing-Yee, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, Meindl, Alfons, Menon, Usha, Milne, Roger L, Muranen, Taru A, and Nevanlinna, Heli

Subjects
Genetics, Cancer, Substance Misuse, Clinical Research, Human Genome, Prevention, Drug Abuse (NIDA only), Breast Cancer, Tobacco, Tobacco Smoke and Health, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundDespite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.MethodsWe applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.ResultsGenetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.ConclusionOur MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

Published
2021

13. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul RHJ, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, and Heiss, Gerardo

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Estrogen, Prevention, Women's Health, Contraception/Reproduction, Aging, Infertility, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Good Health and Well Being, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Europe, Asia, Eastern, Female, Fertility, Fragile X Mental Retardation Protein, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging, Humans, Longevity, Menopause, Menopause, Premature, Mice, Mice, Inbred C57BL, Middle Aged, Ovary, Primary Ovarian Insufficiency, Uterus, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, LifeLines Cohort Study, InterAct consortium, 23andMe Research Team, General Science & Technology
Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021

14. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E, Schoemaker, Minouk J, Gilham, Clare, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Hunter, David J, Jager, Agnes, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, and Olson, Janet E

Subjects
Estrogen, Human Genome, Clinical Research, Cancer, Aging, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Cytochrome P-450 CYP3A, Estrone, Female, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Pregnanediol, Premenopause, Progesterone, Receptors, Estrogen, Receptors, Progesterone, NBCS Collaborators, AOCS Group, ABCTB Investigators, kConFab Investigators, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundEpidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.MethodsWe carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.ResultsFor pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8).ConclusionsThe CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Published
2021

15. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Author

Kramer, Iris, Hooning, Maartje J, Mavaddat, Nasim, Hauptmann, Michael, Keeman, Renske, Steyerberg, Ewout W, Giardiello, Daniele, Antoniou, Antonis C, Pharoah, Paul DP, Canisius, Sander, Abu-Ful, Zumuruda, Andrulis, Irene L, Anton-Culver, Hoda, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Bremer, Michael, Brucker, Sara Y, Burwinkel, Barbara, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, Collée, J Margriet, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hopper, John L, Hou, Ming-Feng, Howell, Anthony, Ito, Hidemi, Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kang, Daehee, Kets, C Marleen, Khusnutdinova, Elza, Ko, Yon-Dschun, Kristensen, Vessela N, Kurian, Allison W, Kwong, Ava, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Matsuo, Keitaro, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger, Mulligan, Anna Marie, Muranen, Taru A, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, and Peto, Julian

Subjects
Breast Cancer, Prevention, Cancer, Adult, Aged, Asian People, Breast Neoplasms, Cohort Studies, Estrogen Receptor alpha, Female, Gene Expression, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Middle Aged, Multifactorial Inheritance, Neoadjuvant Therapy, Neoplasms, Second Primary, Prognosis, Proportional Hazards Models, Receptor, ErbB-2, Receptors, Progesterone, Risk Assessment, White People, NBCS Collaborators, ABCTB Investigators, kConFab Investigators, Receptor, erbB-2, contralateral breast cancer, epidemiology, genetic, polygenic risk score, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Published
2020

16. Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium

Author

Kapoor, Pooja Middha, Lindström, Sara, Behrens, Sabine, Wang, Xiaoliang, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Dunning, Alison M, Pharoah, Paul DP, Schmidt, Marjanka K, Kraft, Peter, García-Closas, Montserrat, Easton, Douglas F, Milne, Roger L, Chang-Claude, Jenny, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bernstein, Leslie, Berrandou, Takiy, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brock, Ian W, Broeks, Annegien, Brooks-Wilson, Angela, Butterbach, Katja, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Clarke, Christine L, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Dite, Gillian S, Earp, H Shelton, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Grundy, Anne, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan E, Harkness, Elaine F, Harstad, Tricia, He, Wei, Heyworth, Jane, Hoover, Robert N, Hopper, John L, Humphreys, Keith, Hunter, David J, Marrón, Pablo Isidro, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Krüger, Ute, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, and Makalic, Enes

Subjects
Genetics, Estrogen, Clinical Research, Cancer, Breast Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Europe, Factor XIII, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, Breast Cancer Association Consortium, Europeans, Gene-environment interaction, breast cancer, epidemiology, risk factors, single nucleotide polymorphism, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundPrevious gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions.MethodsAnalyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions.ResultsNoteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth.ConclusionsOverall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.

Published
2020

17. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Author

Ferreira, Manuel A, Gamazon, Eric R, Al-Ejeh, Fares, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Azzollini, Jacopo, Balmaña, Judith, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Campbell, Ian, Canzian, Federico, Carter, Jonathan, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, Dennis, Joe, Devilee, Peter, Diez, Orland, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, and BCFR Investigators

Subjects
EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Gene Expression Profiling, Quantitative Trait Loci, Female, Genome-Wide Association Study, Prevention, Cancer, Human Genome, Aging, Breast Cancer, Genetics, Biotechnology, 2.1 Biological and endogenous factors
Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Published
2019

18. 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, and Ganz, Patricia A

Subjects
Humans, Breast Neoplasms, Colorectal Neoplasms, Ovarian Neoplasms, Head and Neck Neoplasms, Lung Neoplasms, Prostatic Neoplasms, Genetic Predisposition to Disease, Neoplasm Proteins, Case-Control Studies, Smoking, Mental Disorders, Inheritance Patterns, Phenotype, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Prevention, Cancer, Breast Cancer, Genetics, Rare Diseases, Lung Cancer, Human Genome, Colo-Rectal Cancer, Digestive Diseases, Lung, MD Multidisciplinary
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.

Published
2019

19. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet K, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard T, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, J Esteban, Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan David, Christiansen, Hans, Clarke, Christine L, NBCS Collaborators, Collée, Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, David, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana M, Eilber, Ursula, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, and Huang, Guanmengqian

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Prevention, Breast Cancer, Women's Health, Cancer Genomics, Cancer, 2.1 Biological and endogenous factors, Generic health relevance, Breast Neoplasms, Case-Control Studies, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk, Transcriptome, NBCS Collaborators, kConFab/AOCS Investigators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P

Published
2018

20. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author

Milne, Roger L, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindström, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary, Bolla, Manjeet K, McGuffog, Lesley, Wang, Qin, Aalfs, Cora M, Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittomäki, Kristiina, Al-Ejeh, Fares, Allen, Jamie, Ambrosone, Christine B, Amos, Christopher I, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Auber, Bernd, Auer, Paul L, Ausems, Margreet GEM, Azzollini, Jacopo, Bacot, François, Balmaña, Judith, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B, Barrdahl, Myrto, Barnes, Daniel, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Bignon, Yves-Jean, Blazer, Kathleen R, Blok, Marinus J, Blomqvist, Carl, Blot, William, Bobolis, Kristie, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Bozsik, Aniko, Bradbury, Angela R, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Bressac-de Paillerets, Brigitte, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Brunet, Joan, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byun, Jinyoung, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canzian, Federico, Caron, Olivier, Carracedo, Angel, Carter, Brian D, Castelao, J Esteban, Castera, Laurent, Caux-Moncoutier, Virginie, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Xiaoqing, Cheng, Ting-Yuan David, Chiquette, Jocelyne, Christiansen, Hans, Claes, Kathleen BM, Clarke, Christine L, Conner, Thomas, Conroy, Don M, and Cook, Jackie

Subjects
Biological Sciences, Genetics, Cancer, Human Genome, Prevention, Breast Cancer, Aging, Estrogen, 2.1 Biological and endogenous factors, Aetiology, BRCA1 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, White People, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab/AOCS Investigators, NBSC Collaborators, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Published
2017

21. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Dennis, Joe, Tyrer, Jonathan, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Jean, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Kristensen, Vessela N, Sahlberg, Kristine K, Børresen-Dale, Anne-Lise, Gram, Inger Torhild, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, Alnæs, Grethe I Grenaker, Collée, J Margriet, Lacey, James, Martinez, Elena, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Clarke, Christine, Carpenter, Jane, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Campbell, Ian, De Fazio, Anna, Fox, Stephen, Kirk, Judy, Lindeman, Geoff, Milne, Roger, Southey, Melissa, Spurdle, Amanda, Thorne, Heather, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, Soucy, Penny, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wendt, Camilla, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Simard, Jacques, Dunning, Alison, Pharoah, Paul, Easton, Douglas, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Walker, Logan C [0000-0003-0018-3719], Michailidou, Kyriaki [0000-0001-7065-1237], Wang, Jean [0000-0002-9139-0627], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Behrens, Sabine [0000-0002-9714-104X], Kristensen, Vessela N [0000-0001-5012-7438], Dörk, Thilo [0000-0002-9458-0282], Dossus, Laure [0000-0003-2716-5748], Figueroa, Jonine [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Giles, Graham G [0000-0003-4946-9099], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Johnson, Nichola [0000-0002-8230-5662], Jones, Michael E [0000-0001-7479-3451], Keeman, Renske [0000-0002-5452-9933], Larson, Nicole L [0000-0002-2129-6934], Milne, Roger L [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Olson, Janet E [0000-0003-4944-7789], Peterlongo, Paolo [0000-0001-6951-6855], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Simard, Jacques [0000-0001-6906-3390], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Wilson, Leila [0000-0003-1214-8080], Clinical Genetics, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Clinicum

Subjects
endocrine system diseases, 45/43, Medicine (miscellaneous), Genome-wide association studies, Basic medicine, Breast cancer, Other medical sciences, Runx2, Risk Factors, Biology (General), skin and connective tissue diseases, 0303 health sciences, 030305 genetics & heredity, article, 3. Good health, Female, General Agricultural and Biological Sciences, Medical Genetics, Mutations, DNA Copy Number Variations, Locus, QH301-705.5, kConFab/AOCS Investigators, ABCTB Investigators, 631/208/205/2138, Breast Neoplasms, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, NBCS Collaborators, Association, Deletion, 03 medical and health sciences, SDG 3 - Good Health and Well-being, mental disorders, Humans, 030304 developmental biology, Medicinsk genetik, Cancer och onkologi, Genome, Human, Health sciences, 631/67/1347, CTS Consortium, Germ Cells, Genes, Clinical medicine, Cancer and Oncology, Case-Control Studies, 3111 Biomedicine, Structural variation, Brca1, Genome-Wide Association Study
Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value, Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.

Published
2021

22. Polygenic risk scores for prediction of breast cancer risk in Asian populations

Author

Ho, Weang-Kee, Tai, Mei-Chee, Dennis, Joe, Shu, Xiang, Li, Jingmei, Ho, Peh Joo, Millwood, Iona Y, Lin, Kuang, Jee, Yon-Ho, Lee, Su-Hyun, Mavaddat, Nasim, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Long, Jirong, Wijaya, Eldarina Azfar, Hassan, Tiara, Rahmat, Kartini, Tan, Veronique Kiak Mien, Tan, Benita Kiat Tee, Tan, Su Ming, Tan, Ern Yu, Lim, Swee Ho, Gao, Yu-Tang, Zheng, Ying, Kang, Daehee, Choi, Ji-Yeob, Han, Wonshik, Lee, Han-Byoel, Kubo, Michiki, Okada, Yukinori, Namba, Shinichi, BioBank Japan Project, Park, Sue K, Kim, Sung-Won, Shen, Chen-Yang, Wu, Pei-Ei, Park, Boyoung, Muir, Kenneth R, Lophatananon, Artitaya, Wu, Anna H, Tseng, Chiu-Chen, Matsuo, Keitaro, Ito, Hidemi, Kwong, Ava, Chan, Tsun L, John, Esther M, Kurian, Allison W, Iwasaki, Motoki, Yamaji, Taiki, Kweon, Sun-Seog, Aronson, Kristan J, Murphy, Rachel A, Koh, Woon-Puay, Khor, Chiea-Chuen, Yuan, Jian-Min, Dorajoo, Rajkumar, Walters, Robin G, Chen, Zhengming, Li, Liming, Lv, Jun, Jung, Keum-Ji, Kraft, Peter, Pharoah, Paul DB, Dunning, Alison M, Simard, Jacques, Shu, Xiao-Ou, Yip, Cheng-Har, Taib, Nur Aishah Mohd, Antoniou, Antonis C, Zheng, Wei, Hartman, Mikael, Easton, Douglas F, Teo, Soo-Hwang, Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Multifactorial Inheritance, Bayes Theorem, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk prediction, Breast cancer, Genetic, Polygenic risk score, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, Genome-Wide Association Study
Abstract

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Published
2021
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23. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heiko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, and Hopper, John L

Subjects
Adult, endocrine system diseases, Genotype, Quantitative Trait Loci, ABCTB Investigators, Breast Neoplasms, Linkage Disequilibrium, GEMO Study Collaborators, Risk Factors, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Genetic Testing, Aetiology, Polymorphism, skin and connective tissue diseases, EMBRACE Collaborators, Alleles, HEBON Investigators, Cancer, BRCA2 Protein, BRCA1 Protein, Prevention, Human Genome, Single Nucleotide, Middle Aged, Mutation, Female, KConFab Investigators, Genome-Wide Association Study
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P

Published
2021

24. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author

Zhang, Haoyu, Ahearn, Thomas U, Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O'Mara, Tracy A, Zhao, Ni, Bolla, Manjeet K, Dunning, Alison M, Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auer, Paul L, Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byers, Helen, Caldés, Trinidad, Caligo, Maria A, Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hake, Christopher R, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, and Hillemanns, Peter

Subjects
BRCA1 Protein, Prevention, Human Genome, ABCTB Investigators, Breast Neoplasms, Triple Negative Breast Neoplasms, Biological Sciences, Medical and Health Sciences, Linkage Disequilibrium, GEMO Study Collaborators, EMBRACE Study, Case-Control Studies, Mutation, Breast Cancer, Genetics, kConFab Investigators, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Aetiology, Genome-Wide Association Study, Cancer, Developmental Biology
Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P

Published
2020

25. Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status

Author

Feng, Helian, Gusev, Alexander, Pasaniuc, Bogdan, Wu, Lang, Long, Jirong, Abu-Full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canisius, Sander, Campa, Daniele, Carter, Brian D, Carter, Jonathan, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, de la Hoya, Miguel, De Leeneer, Kim, Dennis, Joe, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hake, Christopher, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Huang, Guanmengqian, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Joseph, Vijai, Jung, Audrey, Karlan, Beth Y, Khusnutdinova, Elza, Kiiski, Johanna I, Konstantopoulou, Irene, Kristensen, Vessela N, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leroux, Dominique, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindor, Noralane, Lindström, Sara, Lo, Wing-Yee, Loud, Jennifer T, Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Martinez, Maria E, Matricardi, Laura, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Kapoor, Pooja M, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna M, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge S, Peixoto, Ana, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Phillips, Kelly-Anne, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Pradhan, Nisha, Prajzendanc, Karolina, Presneau, Nadege, Punie, Kevin, Pylkäs, Katri, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad Usman, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P, Santos, Catarina, Sawyer, Elinor J, Schmidt, Marjanka K, Schmidt, Daniel F, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Rodney J, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Swerdlow, Anthony J, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, van Asperen, Christi J, van den Ouweland, Ans MW, van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vieiro-Balo, Paula, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R, Yannoukakos, Drakoulis, Ziogas, Argyrios, Milne, Roger L, Easton, Douglas F, Chenevix-Trench, Georgia, Zheng, Wei, Kraft, Peter, Jiang, Xia, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Antoniou, Antonis [0000-0001-9223-3116], Barnes, Daniel [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Leslie, Goska [0000-0001-5756-6222], Pharoah, Paul [0000-0001-8494-732X], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Medical Oncology, Clinical Genetics, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Biosciences, Institut Català de la Salut, [Feng H] Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. [Gusev A] Dana‐Farber Cancer Institute, Boston, Massachusetts. [Pasaniuc B] UCLA Path & Lab Med, Los Angeles, California. [Wu L] Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii. [Long J] Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt‐Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. [Abu-full Z] Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Diez O] Hereditary Cancer Genetics Group, Area of Clinical and Molecular Genetics, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Oncology, Epidemiology, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Vesicular Transport Proteins, Estrogen receptor, Genome-wide association study, VARIANTS, Transcriptome, Breast cancer, Brjóstakrabbamein, Receptors, Medicine and Health Sciences, GWAS, skin and connective tissue diseases, Estrogen Receptor Status, Genetics (clinical), Genetics & Heredity, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], 0303 health sciences, Gen, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Causal gene, Genomics, CARRIERS, STATISTICS, 3. Good health, Receptors, Estrogen, breast cancer subtype, causal gene, TWAS, Breast Neoplasms, Estrogens, Female, Genetic Predisposition to Disease, Humans, Risk Assessment, Genome-Wide Association Study, Medical genetics, Breast Cancer Genetics, Erfðarannsóknir, Life Sciences & Biomedicine, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 3122 Cancers, Estrògens, Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Krabbameinsrannsóknir, medicine, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], 030304 developmental biology, Genetic association, Science & Technology, IDENTIFICATION, medicine.disease, Estrogen, TISSUE, Breast cancer subtype, Mama - Càncer - Aspectes genètics, Mathematical & Computational Biology
Abstract

Publisher's version (útgefin grein), Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer., The authors thank the Cellex Foundation for providing research facilities and equipment. The breast cancer genome‐wide association (BCAC) is funded by Cancer Research UK (C1287/A16563, C1287/A10118), the European Union's Horizon 2020 Research and Innovation Programme (grant nos. 634935 and 633784 for BRIDGES and B‐CAST, respectively), and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant no. 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 PSRSIIRI‐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 no. 223175 (HEALTH‐F2‐2009‐223175; COGS), Cancer Research UK (C1287/A10118, C1287/A10710, 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 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 an 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 no. Z01‐CP010119), and the National Institute of Environmental Health Sciences (grant no. 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, 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, E. S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. I. T. is supported by the Oxford Biomedical Research Centre. B. O. C. S. is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). B. O. C. S. 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 were funded in part by grants from the National Cancer Institute (NCI R01CA120120 and K24CA169004). C. B. C. S. is funded by the Canadian Cancer Society (grant no. 313404) and the Canadian Institutes of Health Research. C. C. G. P. 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. Diana Torres 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). The 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. HAC receives 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, 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 Hospital Research Fund, 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 supporting 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 (ALF) 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 (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and the strategic funding of the University of Eastern Finland. The kConFab Follow‐Up Study is supported by grants from Cancer Australia, the Australian National Breast Cancer Foundation, the National Health and Medical Research Council, the National Institute of Health USA, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation Practitioner Fellow. 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, and 199600). G. C. T. and P. W. are supported by the NHMRC. R. B. 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). L. A. A. B. C. is supported by grants (1RB‐0287, 3PB‐0102, 5PB‐0018, and 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 5/1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT‐Institutional strategic projects “5 × 1,000”). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785, and 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. The Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.” The MEC was supported 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. M. S. K. C. C. 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 no. CRN‐87521 and the Ministry of Economic Development, Innovation and Export Trade—grant no. 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. B.‐D. and V. N. K.) and grant 193387/H10 (to A.‐L. B.‐D. and V. N. K.), South‐Eastern Norway Health Authority (grant 39346 to A.‐L.B‐D. and 27208 to V. N. K.) and the Norwegian Cancer Society (to A.‐L. B.‐D. and 419616‐71248‐PR‐2006‐0282 to V. N. K.). 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 no. 250083, 122715 and Center of Excellence grant no. 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 the 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 and 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 no. 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 and IHCC were supported by Grant PBZ_KBN_122/P05/2004 and the program of the Minister of Science and Higher Education under the name “Regional Initiative of Excellence” in 2019–2022 project number 002/RID/2018/19 amount of financing 12,000,000 PLN. The TBCS was funded by The National Cancer Institute of 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 and CA92044) and the Lon V Smith Foundation (LVS39420). The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London and also thank the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. 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), 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 were supported by Hungarian Research Grant KTIA‐OTKA CK‐80745, NKFI_OTKA K‐112228. C. I. received support from the Survey, Recruitment, and Biospecimen 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 Director, 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 ICO study is supported by the Asociación Española Contra el Cáncer (AECC), The Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563, and CIBERONC) and The Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). Dr. Beth Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP‐06‐258‐01‐COUN) and the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000124. A.V. is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds through Research Activity Intensification Program (contract grant nos. INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundación Mutua Madrileña (call 2018). The GEMO resource was initially funded by the French National Institute of Cancer (INCa, PHRC Ile de France, grant AOR 01 082, 2001–2003, grant 2013‐1‐BCB‐01‐ICH‐1), the Association “Le cancer du sein, parlons‐en!” Award (2004) the Association for International Cancer Research (2008–2010), and the Fondation ARC pour la recherche sur le cancer (grant PJA 20151203365). It also received support from the Canadian Institute of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program (2008–2013), and the European commission FP7, Project «Collaborative Ovarian, breast and prostate Gene‐environment Study (COGS), Large‐scale integrating project» (2009–2013). G. E. M. O. is currently supported by the INCa grant SHS‐E‐SP 18‐015. OSUCCC was funded by the Ohio State University Comprehensive Cancer Center. Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, Amber Aielts, and Michelle O'Conor aided in the recruitment of BRCA1/2 study participants and data collection. Robert Pilarski aided in recruitment and data collection of TNBC cases from the Stefanie Spielman Breast Bank. Clinical Genetics Branch, NCI: the Intramural Research Program of the US National Cancer Institute, NIH, Division of Cancer Epidemiology and Genetics, and by support services contracts NO2‐CP‐11019‐50, N02‐CP‐21013‐63 and N02‐CP‐65504 with Westat, Inc, Rockville, MD. ILUH was funded by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, M.K. Schmidt, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam Medical Center, NL: E.J. Meijers‐Heijboer, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez‐Garcia, M.J. Blok, M. de Boer; University of Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo‐ and cyto‐pathology in the Netherlands (PALGA): E.C. van den Broek. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. The HEBON study is supported by the Dutch Cancer Society grants NKI1998‐1854, NKI2004‐3088, NKI2007‐3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014‐187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12‐054. N.N. Petrov Institute of Oncology is supported by the Russian Foundation for Basic Research (grants 17‐00‐00171, 18‐515‐45012 and 19‐515‐25001).

Published
2020

26. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author

Milne, Roger L., Kuchenbaecker, Karoline B., Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindström, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary K, Bolla, Manjeet K., McGuffog, Lesley, Wang, Qin, Aalfs, Cora M., Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittomäki, Kristiina, Al-Ejeh, Fares, Allen, Jamie, Ambrosone, Christine B., Amos, Christopher I, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Auber, Bernd, Auer, Paul L., Ausems, Margreet G E M, Azzollini, Jacopo, Bacot, François, Balmaña, Judith, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B., Barrdahl, Myrto, Barnes, Daniel R, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, and ABCTB Investigators

Subjects
Heterozygote, Receptors, Estrogen, BRCA1 Protein, Risk Factors, European Continental Ancestry Group, Mutation, Journal Article, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Published
2017

27. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author

Feng, Helian, Gusev, Alexander, Pasaniuc, Bogdan, Wu, Lang, Long, Jirong, Abu-Full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canisius, Sander, Campa, Daniele, Carter, Brian D, Carter, Jonathan, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, De Leeneer, Kim, Dennis, Joe, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hake, Christopher, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Huang, Guanmengqian, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Joseph, Vijai, Jung, Audrey, Karlan, Beth Y, Khusnutdinova, Elza, Kiiski, Johanna I, Konstantopoulou, Irene, Kristensen, Vessela N, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leroux, Dominique, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindor, Noralane, Lindström, Sara, Lo, Wing-Yee, Loud, Jennifer T, Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Martinez, Maria E, Matricardi, Laura, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Kapoor, Pooja M, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna M, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge S, Peixoto, Ana, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Phillips, Kelly-Anne, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Pradhan, Nisha, Prajzendanc, Karolina, Presneau, Nadege, Punie, Kevin, Pylkäs, Katri, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad Usman, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P, Santos, Catarina, Sawyer, Elinor J, Schmidt, Marjanka K, Schmidt, Daniel F, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Rodney J, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Swerdlow, Anthony J, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vieiro-Balo, Paula, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R, Yannoukakos, Drakoulis, Ziogas, Argyrios, Milne, Roger L, Easton, Douglas F, Chenevix-Trench, Georgia, Zheng, Wei, Kraft, Peter, and Jiang, Xia

Subjects
causal gene, TWAS, Vesicular Transport Proteins, Breast Neoplasms, Estrogens, Genomics, Risk Assessment, 3. Good health, Receptors, Estrogen, breast cancer subtype, GWAS, Humans, Female, Genetic Predisposition to Disease, Transcriptome, Genome-Wide Association Study
Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

28. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Author

Kramer, Iris, Hooning, Maartje J, Mavaddat, Nasim, Hauptmann, Michael, Keeman, Renske, Steyerberg, Ewout W, Giardiello, Daniele, Antoniou, Antonis C, Pharoah, Paul DP, Canisius, Sander, Abu-Ful, Zumuruda, Andrulis, Irene L, Anton-Culver, Hoda, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Bremer, Michael, Brucker, Sara Y, Burwinkel, Barbara, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, NBCS Collaborators, Collée, J Margriet, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Giles, Graham G, Goldgar, David E, González-Neira, Anna, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hopper, John L, Hou, Ming-Feng, Howell, Anthony, ABCTB Investigators, KConFab Investigators, Ito, Hidemi, Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kang, Daehee, Kets, C Marleen, Khusnutdinova, Elza, Ko, Yon-Dschun, Kristensen, Vessela N, Kurian, Allison W, Kwong, Ava, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Matsuo, Keitaro, Mavroudis, Dimitrios, Meindl, Alfons, Milne, Roger L, Mulligan, Anna Marie, Muranen, Taru A, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Peto, Julian, Petridis, Christos, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Pylkäs, Katri, Radice, Paolo, Rennert, Gad, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schwentner, Lukas, Scott, Christopher, See, Mee-Hoong, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Siesling, Sabine, Slager, Susan, Sohn, Christof, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Tapper, William J, Tengström, Maria, Teo, Soo Hwang, Terry, Mary Beth, Tollenaar, Rob AEM, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Van Ongeval, Chantal, Van Veen, Elke M, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Easton, Douglas F, Hall, Per, and Schmidt, Marjanka K

Subjects
Adult, Multifactorial Inheritance, Receptor, ErbB-2, Gene Expression, Breast Neoplasms, Risk Assessment, White People, Cohort Studies, Asian People, parasitic diseases, Humans, Genetic Predisposition to Disease, Aged, Proportional Hazards Models, Genome, Human, Estrogen Receptor alpha, Neoplasms, Second Primary, Middle Aged, Prognosis, Neoadjuvant Therapy, 3. Good health, polygenic risk score, contralateral breast cancer, epidemiology, Female, genetic, Receptors, Progesterone, Genome-Wide Association Study
Abstract

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

29. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Wu, Lang, Shi, Wei, Long, Jirong, Guo, Xingyi, Michailidou, Kyriaki, Beesley, Jonathan, Bolla, Manjeet K, Shu, Xiao-Ou, Lu, Yingchang, Cai, Qiuyin, Al-Ejeh, Fares, Rozali, Esdy, Wang, Qin, Dennis, Joe, Li, Bingshan, Zeng, Chenjie, Feng, Helian, Gusev, Alexander, Barfield, Richard T, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Barrdahl, Myrto, Baynes, Caroline, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broberg, Per, Brucker, Sara Y, Burwinkel, Barbara, Caldés, Trinidad, Canzian, Federico, Carter, Brian D, Castelao, J Esteban, Chang-Claude, Jenny, Chen, Xiaoqing, Cheng, Ting-Yuan David, Christiansen, Hans, Clarke, Christine L, NBCS Collaborators, Collée, Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, David, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Doheny, Kimberly F, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Eccles, Diana M, Eilber, Ursula, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hallberg, Emily, Hamann, Ute, Harrington, Patricia, Hein, Alexander, Hicks, Belynda, Hillemanns, Peter, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Johnson, Nichola, Jones, Kristine, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kerin, Michael J, Khusnutdinova, Elza, Kosma, Veli-Matti, Kristensen, Vessela N, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindström, Sara, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubinski, Jan, Luccarini, Craig, Lux, Michael P, MacInnis, Robert J, Maishman, Tom, Kostovska, Ivana Maleva, Mannermaa, Arto, Manson, JoAnn E, Margolin, Sara, Mavroudis, Dimitrios, Meijers-Heijboer, Hanne, Meindl, Alfons, Menon, Usha, Meyer, Jeffery, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Nielsen, Sune F, Nordestgaard, Børge G, Olopade, Olufunmilayo I, Olson, Janet E, Olsson, Håkan, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Prentice, Ross, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rahman, Nazneen, Rennert, Gad, Rennert, Hedy S, Rhenius, Valerie, Romero, Atocha, Romm, Jane, Rudolph, Anja, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Scott, Rodney J, Scott, Christopher G, Seal, Sheila, Shah, Mitul, Shrubsole, Martha J, Smeets, Ann, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William, Taylor, Jack A, Terry, Mary Beth, Tessier, Daniel C, Thomas, Abigail, Thöne, Kathrin, Tollenaar, Rob AEM, Torres, Diana, Truong, Thérèse, Untch, Michael, Vachon, Celine, Van Den Berg, David, Vincent, Daniel, Waisfisz, Quinten, Weinberg, Clarice R, Wendt, Camilla, Whittemore, Alice S, Wildiers, Hans, Willett, Walter C, Winqvist, Robert, Wolk, Alicja, Xia, Lucy, Yang, Xiaohong R, Ziogas, Argyrios, Ziv, Elad, KConFab/AOCS Investigators, Dunning, Alison M, Pharoah, Paul DP, Simard, Jacques, Milne, Roger L, Edwards, Stacey L, Kraft, Peter, Easton, Douglas F, Chenevix-Trench, Georgia, and Zheng, Wei

Subjects
Risk, Case-Control Studies, Gene Expression, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Transcriptome, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

30. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E, Schoemaker, Minouk J, Gilham, Clare, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, AOCS Group, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, KConFab Investigators, Jager, Agnes, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S, Ruddy, Kathryn J, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmutzler, Rita K, Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Tamimi, Rulla M, Taylor, Jack A, Tollenaar, Rob AEM, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Van Veen, Elke M, Wang, Sophia S, Weinberg, Clarice R, Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Howie, A Forbes, Peto, Julian, Dos-Santos-Silva, Isabel, Swerdlow, Anthony J, Chang-Claude, Jenny, Schmidt, Marjanka K, Orr, Nick, and Fletcher, Olivia

Subjects
Estrone, Breast Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Premenopause, Receptors, Estrogen, Case-Control Studies, Cytochrome P-450 CYP3A, Humans, Pregnanediol, Female, Receptors, Progesterone, Alleles, Progesterone, Genome-Wide Association Study
Abstract

BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

31. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author

Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, ABCTB Investigators, KConFab/AOCS Investigators, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Krüger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, McLean, Catriona, Meindl, Alfons, Menon, Usha, Nevanlinna, Heli, Newman, William G, Nodora, Jesse, Offit, Kenneth, Olsson, Håkan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V, Peto, Julian, Pita, Guillermo, Plaseska-Karanfilska, Dijana, Prentice, Ross, Punie, Kevin, Pylkäs, Katri, Radice, Paolo, Rennert, Gad, Romero, Atocha, Rüdiger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Schöttker, Ben, Sherman, Mark E, Shu, Xiao-Ou, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Torres, Diana, Troester, Melissa A, Vachon, Celine M, Van Deurzen, Carolien HM, Van Veen, Elke M, Wagner, Philippe, Weinberg, Clarice R, Wendt, Camilla, Wesseling, Jelle, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Couch, Fergus J, Simard, Jacques, Kraft, Peter, Easton, Douglas F, Pharoah, Paul DP, Schmidt, Marjanka K, García-Closas, Montserrat, and Chatterjee, Nilanjan

Subjects
Common breast cancer susceptibility variants, Risk, Receptor, ErbB-2, Genetic predisposition, Etiologic heterogeneity, Breast Neoplasms, 3. Good health, Breast cancer, Receptors, Estrogen, Biomarkers, Tumor, Humans, Female, Receptors, Progesterone, Genome-Wide Association Study
Abstract

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

32. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Ferreira, Manuel A, Gamazon, Eric R, Al-Ejeh, Fares, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Azzollini, Jacopo, Balmaña, Judith, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Campbell, Ian, Canzian, Federico, Carter, Jonathan, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, Dennis, Joe, Devilee, Peter, Diez, Orland, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Joseph, Vijai, Karlan, Beth Y, Khusnutdinova, Elza, Kiiski, Johanna I, Ko, Yon-Dschun, Jones, Michael E, Konstantopoulou, Irene, Kristensen, Vessela N, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindström, Sara, Long, Jirong, Loud, Jennifer T, Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge Sokilde, Peixoto, Ana, Peterlongo, Paolo, Pharoah, Paul DP, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Presneau, Nadege, Radice, Paolo, Rantala, Johanna, Rennert, Gad, Risch, Harvey A, Saloustros, Emmanouil, Sanden, Kristin, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Swerdlow, Anthony J, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Wang, Qin, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R, Yannoukakos, Drakoulis, Ziogas, Argyrios, Kraft, Peter, Antoniou, Antonis C, Zheng, Wei, Easton, Douglas F, Milne, Roger L, Beesley, Jonathan, and Chenevix-Trench, Georgia

Subjects
Gene Expression Profiling, Quantitative Trait Loci, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, 3. Good health, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

33. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author

Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Allen, Jamie, Kar, Siddhartha, Pooley, Karen A, Dennis, Joe, Michailidou, Kyriaki, Turman, Constance, Soucy, Penny, Lemaçon, Audrey, Lush, Michael, Tyrer, Jonathan P, Ghoussaini, Maya, Moradi Marjaneh, Mahdi, Jiang, Xia, Agata, Simona, Aittomäki, Kristiina, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auber, Bernd, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Amie M, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Bosse, Kristin, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brock, Ian W, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Camp, Nicola J, Campbell, Ian, Canzian, Federico, Carroll, Jason S, Carter, Brian D, Castelao, Jose E, Chiquette, Jocelyne, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Droit, Arnaud, Dubois, Stéphane, Dumont, Martine, Duran, Mercedes, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Floris, Giuseppe, Flyger, Henrik, Foretova, Lenka, Foulkes, William D, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Gambino, Gaetana, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Tibiletti, Maria Grazia, Greene, Mark H, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, He, Wei, Healey, Catherine S, Heemskerk-Gerritsen, Bernadette AM, Heyworth, Jane, Hillemanns, Peter, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Hulick, Peter J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Isaacs, Claudine, Iwasaki, Motoki, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Kerin, Michael J, Khusnutdinova, Elza, Kiiski, Johanna I, Kirk, Judy, Kitahara, Cari M, Ko, Yon-Dschun, Konstantopoulou, Irene, Kosma, Veli-Matti, Koutros, Stella, Kubelka-Sabit, Katerina, Kwong, Ava, Kyriacou, Kyriacos, Laitman, Yael, Lambrechts, Diether, Lee, Eunjung, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindblom, Annika, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T, Lubiński, Jan, MacInnis, Robert J, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matsuo, Keitaro, Maurer, Tabea, Mavroudis, Dimitrios, Mayes, Rebecca, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Miller, Nicola, Montagna, Marco, Moreno, Fernando, Muir, Kenneth, Mulligan, Anna Marie, Muñoz-Garzon, Victor M, Muranen, Taru A, Narod, Steven A, Nassir, Rami, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C, Nikitina-Zake, Liene, Norman, Aaron, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Orr, Nick, Osorio, Ana, Pankratz, V Shane, Papp, Janos, Park, Sue K, Park-Simon, Tjoung-Won, Parsons, Michael T, Paul, James, Pedersen, Inge Sokilde, Peissel, Bernard, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Pujana, Miquel Angel, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rau-Murthy, Rohini, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sánchez-Herrero, Estela, Sandler, Dale P, Santamariña, Marta, Saunders, Christobel, Sawyer, Elinor J, Scheuner, Maren T, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schöttker, Ben, Schürmann, Peter, Scott, Christopher, Scott, Rodney J, Senter, Leigha, Seynaeve, Caroline M, Shah, Mitul, Sharma, Priyanka, Shen, Chen-Yang, Shu, Xiao-Ou, Singer, Christian F, Slavin, Thomas P, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony J, Tamimi, Rulla M, Tan, Yen Yen, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Tengström, Maria, Teo, Soo Hwang, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Tzardi, Maria, Ulmer, Hans-Ulrich, Vachon, Celine M, Van Asperen, Christi J, Van Der Kolk, Lizet E, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vijai, Joseph, Vogel, Maartje J, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Hunter, David, Pharoah, Paul DP, Chang-Claude, Jenny, García-Closas, Montserrat, Schmidt, Marjanka K, Milne, Roger L, Kristensen, Vessela N, French, Juliet D, Edwards, Stacey L, Antoniou, Antonis C, Chenevix-Trench, Georgia, Simard, Jacques, Easton, Douglas F, Kraft, Peter, and Dunning, Alison M

Subjects
Quantitative Trait Loci, Chromosome Mapping, Bayes Theorem, Breast Neoplasms, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Risk Factors, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

34. European polygenic risk score for prediction of breast cancer shows similar performance in Asian women

Author

Ho, Weang-Kee, Tan, Min-Min, Mavaddat, Nasim, Tai, Mei-Chee, Mariapun, Shivaani, Li, Jingmei, Ho, Peh-Joo, Dennis, Joe, Tyrer, Jonathan P, Bolla, Manjeet K, Michailidou, Kyriaki, Wang, Qin, Kang, Daehee, Choi, Ji-Yeob, Jamaris, Suniza, Shu, Xiao-Ou, Yoon, Sook-Yee, Park, Sue K, Kim, Sung-Won, Shen, Chen-Yang, Yu, Jyh-Cherng, Tan, Ern Yu, Chan, Patrick Mun Yew, Muir, Kenneth, Lophatananon, Artitaya, Wu, Anna H, Stram, Daniel O, Matsuo, Keitaro, Ito, Hidemi, Chan, Ching Wan, Ngeow, Joanne, Yong, Wei Sean, Lim, Swee Ho, Lim, Geok Hoon, Kwong, Ava, Chan, Tsun L, Tan, Su Ming, Seah, Jaime, John, Esther M, Kurian, Allison W, Koh, Woon-Puay, Khor, Chiea Chuen, Iwasaki, Motoki, Yamaji, Taiki, Tan, Kiak Mien Veronique, Tan, Kiat Tee Benita, Spinelli, John J, Aronson, Kristan J, Hasan, Siti Norhidayu, Rahmat, Kartini, Vijayananthan, Anushya, Sim, Xueling, Pharoah, Paul DP, Zheng, Wei, Dunning, Alison M, Simard, Jacques, Van Dam, Rob Martinus, Yip, Cheng-Har, Taib, Nur Aishah Mohd, Hartman, Mikael, Easton, Douglas F, Teo, Soo-Hwang, and Antoniou, Antonis C

Subjects
Adult, Risk, Multifactorial Inheritance, Asia, Breast Neoplasms, Middle Aged, Prognosis, Polymorphism, Single Nucleotide, 3. Good health, Europe, Case-Control Studies, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
Abstract

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

35. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O'Mara, Tracy A, Dennis, Joe, Tyrer, Jonathan P, Barnes, Daniel R, McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K, Adank, Muriel A, Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heiko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Conroy, Don M, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Eliassen, A Heather, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, He, Wei, Hogervorst, Frans BL, Hollestelle, Antoinette, Hopper, John L, Horcasitas, Darling J, Hulick, Peter J, Hunter, David J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, Agnes, Jakubowska, Anna, James, Paul A, Jensen, Uffe Birk, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I, Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W, Laitman, Yael, Lambrechts, Diether, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T, Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L, Montagna, Marco, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, O'Brien, Katie M, Olopade, Olufunmilayo I, Olson, Janet E, Olsson, Håkan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Phillips, Kelly-Anne, Polley, Eric C, Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P, Santella, Regina, Scheuner, Maren T, Schmidt, Marjanka K, Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Terry, Mary Beth, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Trainer, Alison H, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K, Park, Sue K, Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K, Couch, Fergus J, Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F, Andrieu, Nadine, and Antoniou, Antonis C

Subjects
Adult, BRCA2 Protein, endocrine system diseases, Genotype, BRCA1 Protein, Quantitative Trait Loci, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Risk Factors, Mutation, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Alleles, Genome-Wide Association Study
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

36. 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.

37. Rare germline copy number variants (CNVs) and breast cancer risk

Author

Easton, Douglas, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P [0000-0003-3724-4757], Walker, Logan C [0000-0003-0018-3719], Michailidou, Kyriaki [0000-0001-7065-1237], Wang, Qin [0000-0002-9139-0627], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Behrens, Sabine [0000-0002-9714-104X], Dörk, Thilo [0000-0002-9458-0282], Dossus, Laure [0000-0003-2716-5748], Figueroa, Jonine [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Giles, Graham G [0000-0003-4946-9099], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Johnson, Nichola [0000-0002-8230-5662], Jones, Michael E [0000-0001-7479-3451], Keeman, Renske [0000-0002-5452-9933], Kristensen, Vessela N [0000-0001-5012-7438], Larson, Nicole L [0000-0002-2129-6934], Milne, Roger L [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Olson, Janet E [0000-0003-4944-7789], Peterlongo, Paolo [0000-0001-6951-6855], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Simard, Jacques [0000-0001-6906-3390], Dunning, Alison M [0000-0001-6651-7166], Pharoah, Paul DP [0000-0001-8494-732X], Easton, Douglas F [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Germ Cells, DNA Copy Number Variations, Genome, Human, Risk Factors, Case-Control Studies, Humans, Breast Neoplasms, Female, Genome-Wide Association Study
Abstract

Funder: CIHR, Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Published
2022
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