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1. Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients

Author: Griffin, L, Ho, L, Akhurst, RJ, Arron, ST, Boggs, JME, Conlon, P, O’Kelly, P, Toland, AE, Epstein, EH, Balmain, A, Bastian, BC, Moloney, FJ, Murphy, GM, and Laing, ME
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Health Sciences, Genetics, Cancer, Prevention, Transplantation
Abstract: BackgroundRenal transplant recipients (RTRs) are at increased risk of keratinocyte cancer (KC), especially cutaneous squamous cell carcinoma (cSCC). Previous studies identified a genetic variant of the Methylenetetrahydrofolate Reductase (MTHFR) gene, C677T, which conferred a risk for diagnosis of cSCC in Irish RTRs.ObjectiveWe sought to find further genetic variation in MTHFR and overlap genes that may be associated with a diagnosis of KC in RTRs.MethodsGenotyping of a combined RTR population (n = 821) from two centres, Ireland (n = 546) and the USA (n = 275), was performed. This included 290 RTRs with KC and 444 without. Eleven single nucleotide polymorphisms (SNPs) in the MTHFR gene and seven in the overlap gene MTHFR Chloride transport protein 6 (CLCN6) were evaluated and association explored by time to event analysis (from transplant to first KC) using Cox proportional hazards model.ResultsPolymorphism at MTHFR CLCN6 (rs9651118) was significantly associated with KC in RTRs (HR 1.50, 95% CI 1.17-1.91, p
Published: 2022

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

Author: O'Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, Garcia, MJ, Karlan, BY, De Fazio, A, Bowtell, D, McGuffog, L, Leslie, G, Parsons, MT, Doerk, T, Speith, L-M, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, Mourits, MJE, Lesueur, F, O'Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, Garcia, MJ, Karlan, BY, De Fazio, A, Bowtell, D, McGuffog, L, Leslie, G, Parsons, MT, Doerk, T, Speith, L-M, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, Mourits, MJE, and Lesueur, F
Abstract: BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
Published: 2023

3. Body mass index and molecular subtypes of colorectal cancer.

Author: Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, AI, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, SI, Brenner, H, Buchanan, DD, Cao, Y, Chan, AT, Chen, X, Cheng, I, Chang-Claude, J, Dimou, N, Drew, D, Farris, AB, French, AJ, Gallinger, S, Georgeson, P, Giannakis, M, Giles, GG, Gruber, SB, Harlid, S, Hsu, L, Huang, W-Y, Jenkins, MA, Laskar, RS, Le Marchand, L, Limburg, P, Lin, Y, Mandic, M, Nowak, JA, Obón-Santacana, M, Ogino, S, Qu, C, Sakoda, LC, Schoen, RE, Southey, MC, Stadler, ZK, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Trinh, QM, Tsilidis, KK, Ugai, T, Van Guelpen, B, Wang, X, Woods, MO, Zaidi, SH, Gunter, MJ, Peters, U, Campbell, PT, Murphy, N, Newton, CC, Song, M, Papadimitriou, N, Hoffmeister, M, Phipps, AI, Harrison, TA, Newcomb, PA, Aglago, EK, Berndt, SI, Brenner, H, Buchanan, DD, Cao, Y, Chan, AT, Chen, X, Cheng, I, Chang-Claude, J, Dimou, N, Drew, D, Farris, AB, French, AJ, Gallinger, S, Georgeson, P, Giannakis, M, Giles, GG, Gruber, SB, Harlid, S, Hsu, L, Huang, W-Y, Jenkins, MA, Laskar, RS, Le Marchand, L, Limburg, P, Lin, Y, Mandic, M, Nowak, JA, Obón-Santacana, M, Ogino, S, Qu, C, Sakoda, LC, Schoen, RE, Southey, MC, Stadler, ZK, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Trinh, QM, Tsilidis, KK, Ugai, T, Van Guelpen, B, Wang, X, Woods, MO, Zaidi, SH, Gunter, MJ, Peters, U, and Campbell, PT
Abstract: BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). CONCLUSIONS: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
Published: 2023

4. Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases

Author: Harlid, S, Van Guelpen, B, Qu, C, Gylling, B, Aglago, EK, Amitay, EL, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Moreno, V, Murphy, N, Newcomb, PA, Newton, CC, Nowak, JA, Obon-Santacana, M, Ogino, S, Potter, JD, Song, M, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Ugai, T, Um, CY, Woods, MO, Phipps, A, Harrison, T, Peters, U, Harlid, S, Van Guelpen, B, Qu, C, Gylling, B, Aglago, EK, Amitay, EL, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gunter, MJ, Hoffmeister, M, Hsu, L, Jenkins, MA, Lin, Y, Moreno, V, Murphy, N, Newcomb, PA, Newton, CC, Nowak, JA, Obon-Santacana, M, Ogino, S, Potter, JD, Song, M, Steinfelder, RS, Sun, W, Thibodeau, SN, Toland, AE, Ugai, T, Um, CY, Woods, MO, Phipps, A, Harrison, T, and Peters, U
Abstract: Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.
Published: 2022

5. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, OPAL Study Group, AOCS Group, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, KConFab Investigators, HEBON Investigators, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubiński, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamariña, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, OCAC Consortium, CIMBA Consortium, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, OPAL Study Group, AOCS Group, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, KConFab Investigators, HEBON Investigators, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubiński, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamariña, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, OCAC Consortium, CIMBA Consortium, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Published: 2022

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

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

7. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author: Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, A, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, S, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Lauge, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Yie, JNY, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamarina, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L, Antoniou, AC, Li, S, Silvestri, V, Leslie, G, Rebbeck, TR, Neuhausen, SL, Hopper, JL, Nielsen, HR, Lee, A, Yang, X, McGuffog, L, Parsons, MT, Andrulis, IL, Arnold, N, Belotti, M, Borg, A, Buecher, B, Buys, SS, Caputo, SM, Chung, WK, Colas, C, Colonna, S, Cook, J, Daly, MB, de la Hoya, M, de Pauw, A, Delhomelle, H, Eason, J, Engel, C, Evans, DG, Faust, U, Fehm, TN, Fostira, F, Fountzilas, G, Frone, M, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Gehrig, A, Glendon, G, Goldgar, DE, Golmard, L, Greene, MH, Hahnen, E, Hamann, U, Hanson, H, Hassan, T, Hentschel, J, Horvath, J, Izatt, L, Janavicius, R, Jiao, Y, John, EM, Karlan, BY, Kim, S-W, Konstantopoulou, I, Kwong, A, Lauge, A, Lee, JW, Lesueur, F, Mebirouk, N, Meindl, A, Mouret-Fourme, E, Musgrave, H, Yie, JNY, Niederacher, D, Park, SK, Pedersen, IS, Ramser, J, Ramus, SJ, Rantala, J, Rashid, MU, Reichl, F, Ritter, J, Rump, A, Santamarina, M, Saule, C, Schmidt, G, Schmutzler, RK, Senter, L, Shariff, S, Singer, CF, Southey, MC, Stoppa-Lyonnet, D, Sutter, C, Tan, Y, Teo, SH, Terry, MB, Thomassen, M, Tischkowitz, M, Toland, AE, Torres, D, Vega, A, Wagner, SA, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Spurdle, AB, Easton, DF, Chenevix-Trench, G, Ottini, L, and Antoniou, AC
Abstract: PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.
Published: 2022

8. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author: Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Walker, LC, Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Walker, LC
Abstract: The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
Published: 2022

9. Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Author: Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, S, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, W-Y, Limburg, P, Manson, JE, Moreno, V, Nassir, R, Nowak, JA, Obon-Santacana, M, Ogino, S, Phipps, A, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U, Buchanan, DD, Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, S, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, W-Y, Limburg, P, Manson, JE, Moreno, V, Nassir, R, Nowak, JA, Obon-Santacana, M, Ogino, S, Phipps, A, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U, and Buchanan, DD
Abstract: Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
Published: 2022

10. Association between germline variants and somatic mutations in colorectal cancer.

Author: Barfield, R, Qu, C, Steinfelder, RS, Zeng, C, Harrison, TA, Brezina, S, Buchanan, DD, Campbell, PT, Casey, G, Gallinger, S, Giannakis, M, Gruber, SB, Gsur, A, Hsu, L, Huyghe, JR, Moreno, V, Newcomb, PA, Ogino, S, Phipps, AI, Slattery, ML, Thibodeau, SN, Trinh, QM, Toland, AE, Hudson, TJ, Sun, W, Zaidi, SH, Peters, U, Barfield, R, Qu, C, Steinfelder, RS, Zeng, C, Harrison, TA, Brezina, S, Buchanan, DD, Campbell, PT, Casey, G, Gallinger, S, Giannakis, M, Gruber, SB, Gsur, A, Hsu, L, Huyghe, JR, Moreno, V, Newcomb, PA, Ogino, S, Phipps, AI, Slattery, ML, Thibodeau, SN, Trinh, QM, Toland, AE, Hudson, TJ, Sun, W, Zaidi, SH, and Peters, U
Abstract: Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.
Published: 2022

11. The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author: Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmana, J, Barrowdale, D, Benitez, J, Borg, A, Caldes, T, Caligo, MA, Chung, WK, Claes, KBM, Collee, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, Jiao, Y, John, EM, Joseph, V, Karlan, BY, Kets, CM, Konstantopoulou, I, Kwong, A, Legrand, C, Leslie, G, Lesueur, F, Loud, JT, Lubinski, J, Manoukian, S, McGuffog, L, Miller, A, Gomes, DM, Montagna, M, Mouret-Fourme, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Olah, E, Olopade, OI, Park, SK, Parsons, MT, Peterlongo, P, Piedmonte, M, Radice, P, Rantala, J, Rennert, G, Risch, HA, Schmutzler, RK, Sharma, P, Simard, J, Singer, CF, Stadler, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Teule, A, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tung, N, van Rensburg, EJ, Vega, A, Wappenschmidt, B, Devilee, P, van Asperen, CJ, Bernstein, JL, Offit, K, Easton, DF, Rookus, MA, Chenevix-Trench, G, Antoniou, AC, Robson, M, Schmidt, MK, Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmana, J, Barrowdale, D, Benitez, J, Borg, A, Caldes, T, Caligo, MA, Chung, WK, Claes, KBM, Collee, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, Jiao, Y, John, EM, Joseph, V, Karlan, BY, Kets, CM, Konstantopoulou, I, Kwong, A, Legrand, C, Leslie, G, Lesueur, F, Loud, JT, Lubinski, J, Manoukian, S, McGuffog, L, Miller, A, Gomes, DM, Montagna, M, Mouret-Fourme, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Olah, E, Olopade, OI, Park, SK, Parsons, MT, Peterlongo, P, Piedmonte, M, Radice, P, Rantala, J, Rennert, G, Risch, HA, Schmutzler, RK, Sharma, P, Simard, J, Singer, CF, Stadler, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Teule, A, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tung, N, van Rensburg, EJ, Vega, A, Wappenschmidt, B, Devilee, P, van Asperen, CJ, Bernstein, JL, Offit, K, Easton, DF, Rookus, MA, Chenevix-Trench, G, Antoniou, AC, Robson, M, and Schmidt, MK
Abstract: PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
Published: 2021

12. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Published: 2021

13. Association Between Smoking and Molecular Subtypes of Colorectal Cancer

Author: Wang, X, Amitay, E, Harrison, TA, Banbury, BL, Berndt, S, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Gallinger, SJ, Giannakis, M, Giles, GG, Gunter, MJ, Hopper, JL, Jenkins, MA, Lin, Y, Moreno, V, Nishihara, R, Newcomb, PA, Ogino, S, Phipps, A, Sakoda, LC, Schoen, RE, Slattery, ML, Song, M, Sun, W, Thibodeau, SN, Toland, AE, Van Guelpen, B, Woods, MO, Hsu, L, Hoffmeister, M, Peters, U, Wang, X, Amitay, E, Harrison, TA, Banbury, BL, Berndt, S, Brenner, H, Buchanan, DD, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Gallinger, SJ, Giannakis, M, Giles, GG, Gunter, MJ, Hopper, JL, Jenkins, MA, Lin, Y, Moreno, V, Nishihara, R, Newcomb, PA, Ogino, S, Phipps, A, Sakoda, LC, Schoen, RE, Slattery, ML, Song, M, Sun, W, Thibodeau, SN, Toland, AE, Van Guelpen, B, Woods, MO, Hsu, L, Hoffmeister, M, and Peters, U
Abstract: BACKGROUND: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. METHODS: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. RESULTS: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P trend < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P difference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P difference < .001). CONCLUSION: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
Published: 2021

14. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

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, Aittomaki, 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, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, 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, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, 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, Fox, S, van der Hout, AH, Clarke, C, 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, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, 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, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, 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, Teule, 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, Antoniou, AC, 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, Aittomaki, 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, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, 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, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, 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, Fox, S, van der Hout, AH, Clarke, C, 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, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, 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, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, 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, Teule, 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
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

15. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author: Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, Fletcher, O, Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, and Fletcher, O
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
Published: 2021

16. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author: Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, Peters, U, Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, and Peters, U
Abstract: OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
Published: 2021

17. 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, GEMO Study Collaborators, EMBRACE Collaborators, 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, KConFab Investigators, HEBON Investigators, ABCTB Investigators, 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, Y-D, Kosma, V-M, 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, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, 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, Antoniou, AC, 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, GEMO Study Collaborators, EMBRACE Collaborators, 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, KConFab Investigators, HEBON Investigators, ABCTB Investigators, 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, Y-D, Kosma, V-M, 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, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, 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
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

18. Author Correction: 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, GEMO Study Collaborators, EMBRACE Collaborators, 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, KConFab Investigators, HEBON Investigators, ABCTB Investigators, 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, Y-D, Kosma, V-M, 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, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, 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, Antoniou, AC, 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, GEMO Study Collaborators, EMBRACE Collaborators, 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, KConFab Investigators, HEBON Investigators, ABCTB Investigators, 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, Y-D, Kosma, V-M, 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, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, 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
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

19. 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, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, 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, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, 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, X-O, 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
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. 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

20. Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer

Author: Archambault, AN, Su, Y-R, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Duggan, D, Holowatyj, AN, Huyghe, JR, Brenner, H, Cotterchio, M, Bezieau, S, Schmit, SL, Edlund, CK, Southey, MC, MacInnis, RJ, Campbell, PT, Chang-Claude, J, Slattery, ML, Chan, AT, Joshi, AD, Song, M, Cao, Y, Woods, MO, White, E, Weinstein, SJ, Ulrich, CM, Hoffmeister, M, Bien, SA, Harrison, TA, Hampe, J, Li, CI, Schafmayer, C, Offit, K, Pharoah, PD, Moreno, V, Lindblom, A, Wolk, A, Wu, AH, Li, L, Gunter, MJ, Gsur, A, Keku, TO, Pearlman, R, Bishop, DT, Castellvi-Bel, S, Moreira, L, Vodicka, P, Kampman, E, Giles, GG, Albanes, D, Baron, JA, Berndt, SI, Brezina, S, Buch, S, Buchanan, DD, Trichopoulou, A, Severi, G, Chirlaque, M-D, Sanchez, M-J, Palli, D, Kuhn, T, Murphy, N, Cross, AJ, Burnett-Hartman, AN, Chanock, SJ, de la Chapelle, A, Easton, DF, Elliott, F, English, DR, Feskens, EJM, FitzGerald, LM, Goodman, PJ, Hopper, JL, Hudson, TJ, Hunter, DJ, Jacobs, EJ, Joshu, CE, Kury, S, Markowitz, SD, Milne, RL, Platz, EA, Rennert, G, Rennert, HS, Schumacher, FR, Sandler, RS, Seminara, D, Tangen, CM, Thibodeau, SN, Toland, AE, van Duijnhoven, FJB, Visvanathan, K, Vodickova, L, Potter, JD, Mannisto, S, Weigl, K, Figueiredo, J, Martin, V, Larsson, SC, Parfrey, PS, Huang, W-Y, Lenz, H-J, Castelao, JE, Gago-Dominguez, M, Munoz-Garzon, V, Mancao, C, Haiman, CA, Wilkens, LR, Siegel, E, Barry, E, Younghusband, B, Van Guelpen, B, Harlid, S, Zeleniuch-Jacquotte, A, Liang, PS, Du, M, Casey, G, Lindor, NM, Le Marchand, L, Gallinger, SJ, Jenkins, MA, Newcomb, PA, Gruber, SB, Schoen, RE, Hampel, H, Corley, DA, Hsu, L, Peters, U, Hayes, RB, Archambault, AN, Su, Y-R, Jeon, J, Thomas, M, Lin, Y, Conti, DV, Win, AK, Sakoda, LC, Lansdorp-Vogelaar, I, Peterse, EFP, Zauber, AG, Duggan, D, Holowatyj, AN, Huyghe, JR, Brenner, H, Cotterchio, M, Bezieau, S, Schmit, SL, Edlund, CK, Southey, MC, MacInnis, RJ, Campbell, PT, Chang-Claude, J, Slattery, ML, Chan, AT, Joshi, AD, Song, M, Cao, Y, Woods, MO, White, E, Weinstein, SJ, Ulrich, CM, Hoffmeister, M, Bien, SA, Harrison, TA, Hampe, J, Li, CI, Schafmayer, C, Offit, K, Pharoah, PD, Moreno, V, Lindblom, A, Wolk, A, Wu, AH, Li, L, Gunter, MJ, Gsur, A, Keku, TO, Pearlman, R, Bishop, DT, Castellvi-Bel, S, Moreira, L, Vodicka, P, Kampman, E, Giles, GG, Albanes, D, Baron, JA, Berndt, SI, Brezina, S, Buch, S, Buchanan, DD, Trichopoulou, A, Severi, G, Chirlaque, M-D, Sanchez, M-J, Palli, D, Kuhn, T, Murphy, N, Cross, AJ, Burnett-Hartman, AN, Chanock, SJ, de la Chapelle, A, Easton, DF, Elliott, F, English, DR, Feskens, EJM, FitzGerald, LM, Goodman, PJ, Hopper, JL, Hudson, TJ, Hunter, DJ, Jacobs, EJ, Joshu, CE, Kury, S, Markowitz, SD, Milne, RL, Platz, EA, Rennert, G, Rennert, HS, Schumacher, FR, Sandler, RS, Seminara, D, Tangen, CM, Thibodeau, SN, Toland, AE, van Duijnhoven, FJB, Visvanathan, K, Vodickova, L, Potter, JD, Mannisto, S, Weigl, K, Figueiredo, J, Martin, V, Larsson, SC, Parfrey, PS, Huang, W-Y, Lenz, H-J, Castelao, JE, Gago-Dominguez, M, Munoz-Garzon, V, Mancao, C, Haiman, CA, Wilkens, LR, Siegel, E, Barry, E, Younghusband, B, Van Guelpen, B, Harlid, S, Zeleniuch-Jacquotte, A, Liang, PS, Du, M, Casey, G, Lindor, NM, Le Marchand, L, Gallinger, SJ, Jenkins, MA, Newcomb, PA, Gruber, SB, Schoen, RE, Hampel, H, Corley, DA, Hsu, L, Peters, U, and Hayes, RB
Abstract: BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be mo
Published: 2020

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

Author: Zhan, 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, Abu Ful, Z, Aittomaki, 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, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, 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, Doerk, 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, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, 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, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, 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, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, 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, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, 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, Garcia-Closas, M, Zhan, 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, Abu Ful, Z, Aittomaki, 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, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, 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, Doerk, 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, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, 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, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, 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, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, 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, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, 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 Garcia-Closas, M
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 < 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

22. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author: Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstrate, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, Rebbeck, TR, Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstrate, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, and Rebbeck, TR
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Published: 2020

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

Author: Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dorfling, CM, Dumont, M, Eeles, R, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Foretova, L, Fostira, F, Friedlander, M, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gehrig, A, Gerdes, A-M, Gesta, P, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gschwantler-Kaulich, D, Hahnen, E, Hamann, U, Hanson, H, Hentschel, J, Hogervorst, FBL, Hooning, MJ, Horvath, J, Hu, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kast, K, Koudijs, M, Kruse, TA, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Lesueur, F, Liljegren, A, Loud, JT, Lubinski, J, Mai, PL, Manoukian, S, Mari, V, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, A, Montagna, M, Mouret-Fourme, E, Mukherjee, S, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nielsen, FC, Nikitina-Zake, L, Nogues, C, Olah, E, Olopade, O, Ong, K-R, O'Shaughnessy-Kirwan, A, Osorio, A, Ott, C-E, Papi, L, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Peterlongo, P, Pfeiler, G, Phillips, K-A, Prajzendanc, K, Pujana, MA, Radice, P, Ramser, J, Ramus, SJ, Rantala, J, Rennert, G, Risch, HA, Robson, M, Ronlund, K, Salani, R, Schuster, H, Senter, L, Shah, PD, Sharma, P, Side, LE, Singer, CF, Slavin, TP, Soucy, P, Southey, MC, Spurdle, AB, Steinemann, D, Steinsnyder, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Trainer, AH, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Vierstraete, J, Wagner, G, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Yadav, S, Yang, X, Yannoukakos, D, Zimbalatti, D, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dorfling, CM, Dumont, M, Eeles, R, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Foretova, L, Fostira, F, Friedlander, M, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gehrig, A, Gerdes, A-M, Gesta, P, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gschwantler-Kaulich, D, Hahnen, E, Hamann, U, Hanson, H, Hentschel, J, Hogervorst, FBL, Hooning, MJ, Horvath, J, Hu, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kast, K, Koudijs, M, Kruse, TA, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Lesueur, F, Liljegren, A, Loud, JT, Lubinski, J, Mai, PL, Manoukian, S, Mari, V, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, A, Montagna, M, Mouret-Fourme, E, Mukherjee, S, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nielsen, FC, Nikitina-Zake, L, Nogues, C, Olah, E, Olopade, O, Ong, K-R, O'Shaughnessy-Kirwan, A, Osorio, A, Ott, C-E, Papi, L, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Peterlongo, P, Pfeiler, G, Phillips, K-A, Prajzendanc, K, Pujana, MA, Radice, P, Ramser, J, Ramus, SJ, Rantala, J, Rennert, G, Risch, HA, Robson, M, Ronlund, K, Salani, R, Schuster, H, Senter, L, Shah, PD, Sharma, P, Side, LE, Singer, CF, Slavin, TP, Soucy, P, Southey, MC, Spurdle, AB, Steinemann, D, Steinsnyder, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Trainer, AH, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Vierstraete, J, Wagner, G, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Yadav, S, Yang, X, Yannoukakos, D, Zimbalatti, D, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

24. 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, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, 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, Bruening, T, Burwinkel, B, Cai, Q, Caldes, 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, Doerk, 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, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, 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, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, 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, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, 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, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, 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, Jiang, X, Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, 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, Bruening, T, Burwinkel, B, Cai, Q, Caldes, 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, Doerk, 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, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, 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, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, 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, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, 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, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, 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
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.
Published: 2020

25. Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Author: Sarin, KY, Lin, Y, Daneshjou, R, Ziyatdinov, A, Thorleifsson, G, Rubin, A, Pardo Cortes, Luba, Wu, WT, Khavari, PA, Uitterlinden, André, Nijsten, Tamar, Toland, AE, Olafsson, JH, Sigurgeirsson, B, Thorisdottir, K, Jorgensen, E, Whittemore, AS, Kraft, P, Stacey, SN, Stefansson, K, Asgari, MM, Han, JL, Sarin, KY, Lin, Y, Daneshjou, R, Ziyatdinov, A, Thorleifsson, G, Rubin, A, Pardo Cortes, Luba, Wu, WT, Khavari, PA, Uitterlinden, André, Nijsten, Tamar, Toland, AE, Olafsson, JH, Sigurgeirsson, B, Thorisdottir, K, Jorgensen, E, Whittemore, AS, Kraft, P, Stacey, SN, Stefansson, K, Asgari, MM, and Han, JL
Published: 2020

26. Shared heritability and functional enrichment across six solid cancers

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

27. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author: Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guenel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, 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N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Angel Pujana, M, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamarina, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van Rensburg, EJ, van Veen, EM, Vega, A, Viel, A, Wappenschmidt, B, Weitzel, JN, Wendt, C, Wieme, G, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Zorn, KK, Dunning, AM, Lush, M, Wang, Q, McGuffog, L, Parsons, MT, Pharoah, PDP, Fostira, F, Toland, AE, Andrulis, IL, Ramus, SJ, Swerdlow, AJ, Greene, MH, Chung, WK, Milne, RL, Chenevix-Trench, G, Doerk, T, Schmidt, MK, Easton, DF, Radice, P, Hahnen, E, Antoniou, AC, Couch, FJ, Nevanlinna, H, Surralles, J, Peterlongo, P, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Belotti, M, Bertrand, O, Birot, A-M, Buecher, B, Caputo, S, Dupre, A, Fourme, E, Gauthier-Villars, M, Golmard, L, Le Mentec, M, Moncoutier, V, de Pauw, A, Saule, C, Boutry-Kryza, N, Calender, A, Giraud, S, Leone, M, Bressac-de-Paillerets, B, Caron, O, Guillaud-Bataille, M, Bignon, Y-J, Uhrhammer, N, Bonadona, V, Lasset, C, Berthet, P, Castera, L, Vaur, D, Bourdon, V, Nogues, C, Noguchi, T, Popovici, C, Remenieras, A, Sobol, H, Coupier, I, Pujol, P, Adenis, C, Dumont, A, Revillion, F, Muller, D, Barouk-Simonet, E, Bonnet, F, Bubien, V, Longy, M, Sevenet, N, Gladieff, L, Guimbaud, R, Feillel, V, Toulas, C, Dreyfus, H, Leroux, CD, Peysselon, M, Rebischung, C, Legrand, C, Baurand, A, Bertolone, G, Coron, F, Faivre, L, Jacquot, C, Lizard, S, Kientz, C, Lebrun, M, Prieur, F, Fert-Ferrer, S, Mari, V, Venat-Bouvet, L, Bezieau, S, Delnatte, C, Mortemousque, I, Colas, C, Coulet, F, Soubrier, F, Warcoin, M, Bronner, M, Sokolowska, J, Collonge-Rame, M-A, Damette, A, Gesta, P, Lallaoui, H, Chiesa, J, Molina-Gomes, D, Ingster, O, Manouvrier-Hanu, S, Lejeune, S, Aghmesheh, M, Greening, S, Amor, D, Gattas, M, Botes, L, Buckley, M, Friedlander, M, Koehler, J, Meiser, B, Saleh, M, Salisbury, E, Trainer, A, Tucker, K, Antill, Y, Dobrovic, A, Fellows, A, Fox, S, Harris, M, Nightingale, S, Phillips, K, Sambrook, J, Thorne, H, Armitage, S, Arnold, L, Kefford, R, Kirk, J, Rickard, E, Bastick, P, Beesley, J, Hayward, N, Spurdle, A, Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, and Young, MA
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
Published: 2019

28. Two truncating variants in FANCC and breast cancer risk

Author: Dork, T, Peterlongo, P, Mannermaa, A, Bolla, MK, Wang, Q, Dennis, J, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Beckmann, MW, Beeghly-Fadiel, A, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Canzian, F, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiansen, H, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Ekici, AB, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Fritschisl, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hein, A, Hillemanns, P, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Howell, T, Huo, D, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Kang, D, Kapoor, PM, Khusnutdinova, E, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kwon, A, Lambrechts, D, Le Marchand, L, Li, J, Lindstrom, S, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Lubinski, J, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, E, Matsuo, K, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Taib, NAM, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Offit, K, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Peto, J, Plaseska-Karanfilska, D, Pohl-Rescigno, E, Presneau, N, Rack, B, Radice, P, Rashid, MU, Rennert, G, Rennert, HS, Romero, A, Ruebner, M, Saloustros, E, Schmidt, MK, Schmutzler, RK, Schneider, MO, Schoemaker, MJ, Scott, C, Shen, C-Y, Shu, X-O, Simard, J, Slager, S, Smichkoska, S, Southey, MC, Spinelli, JJ, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Tsugane, S, Untch, M, Vachon, CM, van den Ouweland, AMW, van Veen, EM, Vijai, J, Wendt, C, Wolk, A, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Pharoah, PDP, Schindler, D, Devilee, P, Easton, DF, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Borresen-Dale, A-L, Alnaes, GIG, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, Geisler, J, Dork, T, Peterlongo, P, Mannermaa, A, Bolla, MK, Wang, Q, Dennis, J, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Freeman, LEB, Beckmann, MW, Beeghly-Fadiel, A, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Canzian, F, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiansen, H, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Ekici, AB, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Fritschisl, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hein, A, Hillemanns, P, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Howell, T, Huo, D, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Kang, D, Kapoor, PM, Khusnutdinova, E, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kwon, A, Lambrechts, D, Le Marchand, L, Li, J, Lindstrom, S, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Lubinski, J, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, E, Matsuo, K, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Taib, NAM, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Offit, K, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Peto, J, Plaseska-Karanfilska, D, Pohl-Rescigno, E, Presneau, N, Rack, B, Radice, P, Rashid, MU, Rennert, G, Rennert, HS, Romero, A, Ruebner, M, Saloustros, E, Schmidt, MK, Schmutzler, RK, Schneider, MO, Schoemaker, MJ, Scott, C, Shen, C-Y, Shu, X-O, Simard, J, Slager, S, Smichkoska, S, Southey, MC, Spinelli, JJ, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Tsugane, S, Untch, M, Vachon, CM, van den Ouweland, AMW, van Veen, EM, Vijai, J, Wendt, C, Wolk, A, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Pharoah, PDP, Schindler, D, Devilee, P, Easton, DF, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Borresen-Dale, A-L, Alnaes, GIG, Sahlberg, KK, Ottestad, L, Karesen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebraten, O, Naume, B, Fossa, A, Kiserud, CE, Reinertsen, K, Helland, A, Riis, M, and Geisler, J
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Published: 2019

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

Author: Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, Huo, D, Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, and Huo, D
Abstract: BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
Published: 2019

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

Author: Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, and Yip, D
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

31. Discovery of common and rare genetic risk variants for colorectal cancer

Author: Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, Peters, U, Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, and Peters, U
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
Published: 2019

32. Shared heritability and functional enrichment across six solid cancers (vol 10, 431, 2019)

Author: Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, Lindstrom, S, Jiang, X, Finucane, HK, Schumacher, FR, Schmit, SL, Tyrer, JP, Han, Y, Michailidou, K, Lesseur, C, Kuchenbaecker, KB, Dennis, J, Conti, DV, Casey, G, Gaudet, MM, Huyghe, JR, Albanes, D, Aldrich, MC, Andrew, AS, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Antonenkova, NN, Arnold, SM, Aronson, KJ, Arun, BK, Bandera, EV, Barkardottir, RB, Barnes, DR, Batra, J, Beckmann, MW, Benitez, J, Benlloch, S, Berchuck, A, Berndt, SI, Bickeboller, H, Bien, SA, Blomqvist, C, Boccia, S, Bogdanova, NV, Bojesen, SE, Bolla, MK, Brauch, H, Brenner, H, Brenton, JD, Brook, MN, Brunet, J, Brunnstrom, H, Buchanan, DD, Burwinkel, B, Butzow, R, Cadoni, G, Caldes, T, Caligo, MA, Campbell, I, Campbell, PT, Cancel-Tassin, G, Cannon-Albright, L, Campa, D, Caporaso, N, Carvalho, AL, Chan, AT, Chang-Claude, J, Chanock, SJ, Chen, C, Christiani, DC, Claes, KBM, Claessens, F, Clements, J, Collee, JM, Correa, MC, Couch, FJ, Cox, A, Cunningham, JM, Cybulski, C, Czene, K, Daly, MB, deFazio, A, Devilee, P, Diez, O, Gago-Dominguez, M, Donovan, JL, Dork, T, Duell, EJ, Dunning, AM, Dwek, M, Eccles, DM, Edlund, CK, Edwards, DRV, Ellberg, C, Evans, DG, Fasching, PA, Ferris, RL, Liloglou, T, Figueiredo, JC, Fletcher, O, Fortner, RT, Fostira, F, Franceschi, S, Friedman, E, Gallinger, SJ, Ganz, PA, Garber, J, Garcia-Saenz, JA, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Goode, EL, Goodman, MT, Goodman, G, Grankvist, K, Greene, MH, Gronberg, H, Gronwald, J, Guenel, P, Hakansson, N, Hall, P, Hamann, U, Hamdy, FC, Hamilton, RJ, Hampe, J, Haugen, A, Heitz, F, Herrero, R, Hillemanns, P, Hoffmeister, M, Hogdall, E, Hong, Y-C, Hopper, JL, Houlston, R, Hulick, PJ, Hunter, DJ, Huntsman, DG, Idos, G, Imyanitov, EN, Ingles, SA, Isaacs, C, Jakubowska, A, James, P, Jenkins, MA, Johansson, M, John, EM, Joshi, AD, Kaneva, R, Karlan, BY, Kelemen, LE, Kuehl, T, Khaw, K-T, Khusnutdinova, E, Kibel, AS, Kiemeney, LA, Kim, J, Kjaer, SK, Knight, JA, Kogevinas, M, Kote-Jarai, Z, Koutros, S, Kristensen, VN, Kupryjanczyk, J, Lacko, M, Lam, S, Lambrechts, D, Landi, MT, Lazarus, P, Le, ND, Lee, E, Lejbkowicz, F, Lenz, H-J, Leslie, G, Lessel, D, Lester, J, Levine, DA, Li, L, Li, CI, Lindblom, A, Lindor, NM, Liu, G, Loupakis, F, Lubinski, J, Maehle, L, Maier, C, Mannermaa, A, Le Marchand, L, Margolin, S, May, T, McGuffog, L, Meindl, A, Middha, P, Miller, A, Milne, RL, MacInnis, RJ, Modugno, F, Montagna, M, Moreno, V, Moysich, KB, Mucci, L, Muir, K, Mulligan, AM, Nathanson, KL, Neal, DE, Ness, AR, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Newcomb, LF, Nielsen, FC, Nikitina-Zake, L, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Al Olama, AA, Olopade, OI, Olshan, AF, Olsson, H, Osorio, A, Pandha, H, Park, JY, Pashayan, N, Parsons, MT, Pejovic, T, Penney, KL, Peters, WHM, Phelan, CM, Phipps, AI, Plaseska-Karanfilska, D, Pring, M, Prokofyeva, D, Radice, P, Stefansson, K, Ramus, SJ, Raskin, L, Rennert, G, Rennert, HS, van Rensburg, EJ, Riggan, MJ, Risch, HA, Risch, A, Roobol, MJ, Rosenstein, BS, Rossing, MA, De Ruyck, K, Saloustros, E, Sandler, DP, Sawyer, EJ, Schabath, MB, Schleutker, J, Schmidt, MK, Setiawan, VW, Shen, H, Siegel, EM, Sieh, W, Singer, CF, Slattery, ML, Sorensen, KD, Southey, MC, Spurdle, AB, Stanford, JL, Stevens, VL, Stintzing, S, Stone, J, Sundfeldt, K, Sutphen, R, Swerdlow, AJ, Tajara, EH, Tangen, CM, Tardon, A, Taylor, JA, Teare, MD, Teixeira, MR, Terry, MB, Terry, KL, Thibodeau, SN, Thomassen, M, Bjorge, L, Tischkowitz, M, Toland, AE, Torres, D, Townsend, PA, Travis, RC, Tung, N, Tworoger, SS, Ulrich, CM, Usmani, N, Vachon, CM, Van Nieuwenhuysen, E, Vega, A, Elias Aguado-Barrera, M, Wang, Q, Webb, PM, Weinberg, CR, Weinstein, S, Weissler, MC, Weitzel, JN, West, CML, White, E, Whittemore, AS, Wichmann, H-E, Wiklund, F, Winqvist, R, Wolk, A, Woll, P, Woods, M, Wu, AH, Wu, X, Yannoukakos, D, Zheng, W, Zienolddiny, S, Ziogas, A, Zorn, KK, Lane, JM, Saxena, R, Thomas, D, Hung, RJ, Diergaarde, B, McKay, J, Peters, U, Hsu, L, Garcia-Closas, M, Eeles, RA, Chenevix-Trench, G, Brennan, PJ, Haiman, CA, Simard, J, Easton, DF, Gruber, SB, Pharoah, PDP, Price, AL, Pasaniuc, B, Amos, CI, Kraft, P, and Lindstrom, S
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

33. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author: Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, Spurdle, AB, Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, and Spurdle, AB
Abstract: The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
Published: 2019

34. The BRCA2 c.68‐7T > A variant is not pathogenic:a model for clinical calibration of spliceogenicity

Author: Colombo, M, Lopez-Perolio, I, Meeks, H D, Caleca, L, Parsons, MT, Li, HY, De Vecchi, G, Tudini, E, Foglia, C, Mondini, P, Manoukian, S, Behar, R, Garcia, EBG, Meindl, A, Montagna, M, Niederacher, D, Schmidt, AY, Varesco, L, Wappenschmidt, B, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadel, A, Benitez, J, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Chang-Claude, J, Conroy, D M, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Eriksson, M, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hollestelle, Antoinette, Hopper, JL, Jakubowska, A, Jung, A, Kosma, VM, Lambrechts, D, Le Marchand, L, Lindblom, A, Lubinski, J, Mannermaa, A, Margolin, S, Miao, H, Milne, RL, Neuhausen, SL, Nevanlinna, H, Olson, JE, Peterlongo, P, Peto, J, Pylkas, K, Sawyer, EJ, Schmidt, MK (Marjanka), Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, See, MH, Southey, MC, Swerdlow, A, Teo, SH, Toland, AE, Tomlinson, I, Truong, T, van Asperen, CJ, van den Ouweland, Ans, van der Kolk, LE, Winqvist, R, Yannoukakos, D, Zheng, W, Dunning, AM, Easton, DF, Henderson, A, Hogervorst, FBL, Izatt, L, Offitt, K, Side, LE, van Rensburg, EJ, McGuffog, L, Antoniou, AC, Chenevix-Trench, G, Spurdle, AB, Goldgar, DE, de la Hoya, M, Radice, P, Medical Oncology, and Clinical Genetics
Subjects: digital PCR, multifactorial likelihood analysis, spliceogenic variants, quantitative real-time PCR, BRCA2
Abstract: Although the spliceogenic nature of the BRCA2 c.68‐7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real‐time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case‐control analysis in 83,636 individuals. Co‐occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5‐fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68‐7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10⁻¹¹⁵. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86–1.24) nor for a deleterious effect of the variant when co‐occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68‐7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018

35. The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Author: Colombo, M, Lopez-Perolio, I, Meeks, HD, Caleca, L, Parsons, MT, Li, H, De Vecchi, G, Tudini, E, Foglia, C, Mondini, P, Manoukian, S, Behar, R, Garcia, EBG, Meindl, A, Montagna, M, Niederacher, D, Schmidt, AY, Varesco, L, Wappenschmidt, B, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadel, A, Benitez, J, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Chang-Claude, J, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Eriksson, M, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hollestelle, A, Hopper, JL, Jakubowska, A, Jung, A, Kosma, V-M, Lambrechts, D, Le Marchand, L, Lindblom, A, Lubinski, J, Mannermaa, A, Margolin, S, Miao, H, Milne, RL, Neuhausen, SL, Nevanlinna, H, Olson, JE, Peterlongo, P, Peto, J, Pylkas, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, See, MH, Southey, MC, Swerdlow, A, Teo, SH, Toland, AE, Tomlinson, I, Truong, T, van Asperen, CJ, van den Ouweland, AMW, van der Kolk, LE, Winqvist, R, Yannoukakos, D, Zheng, W, Dunning, AM, Easton, DF, Henderson, A, Hogervorst, FBL, Izatt, L, Offitt, K, Side, LE, van Rensburg, EJ, McGuffog, L, Antoniou, AC, Chenevix-Trench, G, Spurdle, AB, Goldgar, DE, de la Hoya, M, Radice, P, Colombo, M, Lopez-Perolio, I, Meeks, HD, Caleca, L, Parsons, MT, Li, H, De Vecchi, G, Tudini, E, Foglia, C, Mondini, P, Manoukian, S, Behar, R, Garcia, EBG, Meindl, A, Montagna, M, Niederacher, D, Schmidt, AY, Varesco, L, Wappenschmidt, B, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadel, A, Benitez, J, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Chang-Claude, J, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Eriksson, M, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hollestelle, A, Hopper, JL, Jakubowska, A, Jung, A, Kosma, V-M, Lambrechts, D, Le Marchand, L, Lindblom, A, Lubinski, J, Mannermaa, A, Margolin, S, Miao, H, Milne, RL, Neuhausen, SL, Nevanlinna, H, Olson, JE, Peterlongo, P, Peto, J, Pylkas, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, See, MH, Southey, MC, Swerdlow, A, Teo, SH, Toland, AE, Tomlinson, I, Truong, T, van Asperen, CJ, van den Ouweland, AMW, van der Kolk, LE, Winqvist, R, Yannoukakos, D, Zheng, W, Dunning, AM, Easton, DF, Henderson, A, Hogervorst, FBL, Izatt, L, Offitt, K, Side, LE, van Rensburg, EJ, McGuffog, L, Antoniou, AC, Chenevix-Trench, G, Spurdle, AB, Goldgar, DE, de la Hoya, M, and Radice, P
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018

36. Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies

Author: Toland, AE, Pande, M, Joon, A, Brewster, AM, Chen, WV, Hoppers, JL, Eng, C, Shete, S, Casey, G, Schumacher, F, Lin, Y, Harrison, TA, White, E, Ahsan, H, Andrulis, IL, Whittemore, AS, John, EM, Win, AK, Makalic, E, Schmidt, DF, Kapuscinski, MK, Ochs-Balcom, HM, Gallinger, S, Jenkins, MA, Newcomb, PA, Lindor, NM, Peters, U, Amos, CI, Lynch, PM, Toland, AE, Pande, M, Joon, A, Brewster, AM, Chen, WV, Hoppers, JL, Eng, C, Shete, S, Casey, G, Schumacher, F, Lin, Y, Harrison, TA, White, E, Ahsan, H, Andrulis, IL, Whittemore, AS, John, EM, Win, AK, Makalic, E, Schmidt, DF, Kapuscinski, MK, Ochs-Balcom, HM, Gallinger, S, Jenkins, MA, Newcomb, PA, Lindor, NM, Peters, U, Amos, CI, and Lynch, PM
Abstract: BACKGROUND: Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. METHODS: To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls). RESULTS: Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). CONCLUSION: The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.
Published: 2018

37. Validation of a genetic risk score for Arkansas women of color

Author: Toland, AE, Starlard-Davenport, A, Allman, R, Dite, GS, Hopper, JL, Tuff, ES, Macleod, S, Kadlubar, S, Preston, M, Henry-Tillman, R, Toland, AE, Starlard-Davenport, A, Allman, R, Dite, GS, Hopper, JL, Tuff, ES, Macleod, S, Kadlubar, S, Preston, M, and Henry-Tillman, R
Abstract: African American women in the state of Arkansas have high breast cancer mortality rates. Breast cancer risk assessment tools developed for African American underestimate breast cancer risk. Combining African American breast cancer associated single-nucleotide polymorphisms (SNPs) into breast cancer risk algorithms may improve individualized estimates of a woman's risk of developing breast cancer and enable improved recommendation of screening and chemoprevention for women at high risk. The goal of this study was to confirm with an independent dataset consisting of Arkansas women of color, whether a genetic risk score derived from common breast cancer susceptibility SNPs can be combined with a clinical risk estimate provided by the Breast Cancer Risk Assessment Tool (BCRAT) to produce a more accurate individualized breast cancer risk estimate. A population-based cohort of African American women representative of Arkansas consisted of 319 cases and 559 controls for this study. Five-year and lifetime risks from the BCRAT were measured and combined with a risk score based on 75 independent susceptibility SNPs in African American women. We used the odds ratio (OR) per adjusted standard deviation to evaluate the improvement in risk estimates produced by combining the polygenic risk score (PRS) with 5-year and lifetime risk scores estimated using BCRAT. For 5-year risk OR per standard deviation increased from 1.84 to 2.08 with the addition of the polygenic risk score and from 1.79 to 2.07 for the lifetime risk score. Reclassification analysis indicated that 13% of cases had their 5-year risk increased above the 1.66% guideline threshold (NRI = 0.020 (95% CI -0.040, 0.080)) and 6.3% of cases had their lifetime risk increased above the 20% guideline threshold by the addition of the polygenic risk score (NRI = 0.034 (95% CI 0.000, 0.070)). Our data confirmed that discriminatory accuracy of BCRAT is improved for African American women in Arkansas with the inclusion of specific
Published: 2018

38. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Nathanson, KL, Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Nathanson, KL
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018

39. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

Author: Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnæs, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Perez, JIA, Menéndez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnæs, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Rosario Alonso, M, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
Abstract: This corrects the article DOI: 10.1038/ncomms5999.
Published: 2018

40. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author: Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemacon, A, Adlard, J, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sonderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teule, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC, Simard, J, Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemacon, A, Adlard, J, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sonderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teule, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC, and Simard, J
Abstract: PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
Published: 2017

41. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author: Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, Ottini, L, Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, and Ottini, L
Abstract: Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Published: 2017

42. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Pfeiler, G, Vigorito, E, Kuchenbaecker, KB, Beesley, J, Adlard, J, Agnarsson, BA, Andrulis, IL, Arun, BK, Barjhoux, L, Belotti, M, Benitez, J, Berger, A, Phelan, CM, Piedmonte, M, Poppe, B, Pujana, MA, Radice, P, Rennert, G, Rodriguez, GC, Rookus, MA, Ross, EA, Bojesen, A, Schmutzler, RK, Simard, J, Singer, CF, Slavin, TP, Soucy, P, Southey, M, Steinemann, D, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Bonanni, B, Szabo, CI, Tea, MK, Teixeira, MR, Teo, SH, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, van Rensburg, EJ, Brewer, C, Varesco, L, Varon-Mateeva, R, Vratimos, A, Weitzel, JN, McGuffog, L, Kirk, J, Toland, AE, Hamann, U, Lindor, N, Ramus, SJ, Caldes, T, Greene, MH, Couch, FJ, Offit, K, Pharoah, PDP, Chenevix-Trench, G, Antoniou, AC, Prokunina-Olsson, L, Caligo, MA, Campbell, I, Chan, SB, Claes, KBM, Cohn, DE, Cook, J, Daly, MB, Damiola, F, Davidson, R, Pauw, AD, Delnatte, C, Diez, O, Domchek, SM, Dumont, M, Durda, K, Dworniczak, B, Easton, DF, Eccles, D, Edwinsdotter Ardnor, C, Eeles, R, Ejlertsen, B, Ellis, S, Evans, G, Feliubadalo, L, Fostira, F, Foulkes, WD, Friedman, E, Frost, D, Gaddam, P, Ganz, PA, Garber, J, Garcia-Barberan, V, Gauthier-Villars, M, Gehrig, A, Gerdes, AM, Giraud, S, Godwin, AK, Goldgar, DE, Hake, CR, Hansen, TVO, Healey, S, Hodgson, S, Hogervorst, FBL, Houdayer, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jacobs, L, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Vijai, J, Karlan, BY, Kast, K, Investigators, K, Khan, S, Kwong, A, Laitman, Y, Lester, J, Lesueur, F, Liljegren, A, Lubinski, J, Mai, PL, Manoukian, S, Mazoyer, S, Meindl, A, Mensenkamp, AR, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Olah, E, Olopade, OI, Ong, KR, Osorio, A, Park, SK, Paulsson-Karlsson, Y, Pedersen, IS, Peissel, B, and Peterlongo, P
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA 1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population
Published: 2016

43. Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

Author: Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, X, Barrowdale, D, De Garibay, GR, Librado, P, Sánchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Català, I, Brunet, J, Feliubadaló, L, Tornero, E, Benítez, J, Osorio, A, Teresa, R, Teresa, C, Nevanlinna, H, Aittomäki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Díez, O, Hansen, TV, Jønson, L, Gerdes, AM, Ejlertsen, B, De La Hoya, M, Caldés, T, Dunning, AM, Oliver, C, Fineberg, E, Cook, M, Peock, S, McCann, E, Murray, A, Jacobs, C, Pichert, G, Lalloo, F, Chu, C, Dorkins, H, Paterson, J, Ong, KR, Teixeira, MR, Teixeira, T, Hogervorst, FBL, Van Der Hout, AH, Seynaeve, C, Van Der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, Van Den Ouweland, AMW, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, and Wang-Gohrke, S
Subjects: skin and connective tissue diseases
Abstract: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 × 10-4(false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteractionvalues > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
Published: 2015

44. Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair EDITORIAL COMMENT

Author: Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, Lisette, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, Huffman, JE, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, Najaf, Corre, T, Hottenga, JJ (Jouke Jan), Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, AL, Boutin, TS, Brauch, H, Brenner, H, Bruning, T, Burwinkel, B, Campbell, A (Archie), Campbell, H, Chanock, SJ, Chapman, JR, Chen, YDI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, de Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Dork, T, dos-Santos-Silva, I, Dunning, AM, Eicher, JD, Fasching, PA, Faul, JD, Figueroa, J, Flesch-Janys, D, Gandin, I, Garcia, ME, Garcia-Closas, M, Giles, GG, Girotto, GG, Goldberg, MS, Gonzalez-Neira, A, Goodarzi, MO, Grove, ML, Gudbjartsson, DF, Guenel, P, Guo, XQ, Haiman, CA, Hall, P, Hamann, U, Henderson, BE, Hocking, LJ, Hofman, Bert, Homuth, G, Hooning, Maartje, Hopper, JL, Hu, FB, Huang, JY, Humphreys, K, Hunter, DJ, Jakubowska, A, Jones, SE, Kabisch, M, Karasik, D, Knight, JA, Kolcic, I, Kooperberg, C, Kosma, VM, Kriebel, J, Kristensen, V, Lambrechts, D, Langenberg, C, Li, JM, Li, X, Lindstrom, S, Liu, YM, Luan, JA, Lubinski, J, Magi, R, Mannermaa, A, Manz, J, Margolin, S, Marten, J, Martin, NG, Masciullo, C, Meindl, A, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Muller-Nurasyid, M, Nalls, M, Neale, BM, Nevanlinna, H, Neven, P, Newman, AB, Nordestgaard, BG, Olson, JE, Padmanabhan, S, Peterlongo, P, Peters, U, Petersmann, A, Peto, J, Pharoah, PDP, Pirastu, NN, Pirie, A, Pistis, G, Polasek, O, Porteous, D, Psaty, BM, Pylkas, K, Radice, P, Raffel, LJ, Rivadeneira, Fernando, Rudan, I, Rudolph, A, Ruggiero, D, Sala, CF, Sanna, S, Sawyer, EJ, Schlessinger, D, Schmidt, MK (Marjanka), Schmidt, F, Schmutzler, RK, Schoemaker, MJ, Scott, RA, Seynaeve, Caroline, Simard, J, Sorice, R, Southey, MC, Stockl, D, Strauch, K, Swerdlow, A, Taylor, KD, Thorsteinsdottir, U, Toland, AE, Tomlinson, I, Truong, T, Tryggvadottir, L, Turner, ST, Vozzi, D, Wang, Q (Qing), Wellons, M, Willemsen, G, Wilson, JF, Winqvist, R, Wolffenbuttel, BBHR, Wright, AF, Yannoukakos, D, Zemunik, T, Zheng, W, Zygmunt, M, Bergmann, S, Boomsma, DI, Buring, JE, Ferrucci, L, Montgomery, GW, Gudnason, V, Spector, TD, Duijn, Cornelia, Alizadeh, BZ, Ciullo, M, Crisponi, L, Easton, DF, Gasparini, PP, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, AC, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, André, Ulivi, S, Volzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, LM, Price, AL, Stefansson, K, Visser, Jenny, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB, Murray, A, Systems Ecology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Internal Medicine, Epidemiology, Medical Oncology, and Clinical Genetics
Subjects: SDG 3 - Good Health and Well-being
Published: 2015

45. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author: Spurdle, AB, Couch, FJ, Parsons, MT, McGuffog, L, Barrowdale, D, Bolla, MK, Wang, Q, Healey, S, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Hahnen, E, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Ellis, S, Frost, D, Platte, R, Perkins, J, Gareth Evans, D, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Cole, T, Scuvera, G, Manoukian, S, Bonanni, B, Mariette, F, Fortuzzi, S, Viel, A, Pasini, B, Papi, L, Varesco, L, Balleine, R, Nathanson, KL, Domchek, SM, Offitt, K, Jakubowska, A, Lindor, N, Thomassen, M, Jensen, UB, Rantala, J, Borg, Å, Andrulis, IL, Miron, A, Hansen, TVO, Caldes, T, Neuhausen, SL, Toland, AE, Nevanlinna, H, Montagna, M, Garber, J, Godwin, AK, Osorio, A, Factor, RE, Terry, MB, Rebbeck, TR, Karlan, BY, Southey, M, Rashid, MU, Tung, N, Pharoah, PDP, Blows, FM, Dunning, AM, Provenzano, E, Hall, P, Czene, K, Schmidt, MK, Broeks, A, Cornelissen, S, Verhoef, S, Fasching, PA, Beckmann, MW, Ekici, AB, Slamon, DJ, Bojesen, SE, and Nordestgaard, BG
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: © 2014 Spurdle et al. Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Published: 2014

46. Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry

Author: Toland, AE, Scott, CM, Joo, JE, O'Callaghan, N, Buchanan, DD, Clendenning, M, Giles, GG, Hopper, JL, Wong, EM, Southey, MC, Toland, AE, Scott, CM, Joo, JE, O'Callaghan, N, Buchanan, DD, Clendenning, M, Giles, GG, Hopper, JL, Wong, EM, and Southey, MC
Abstract: DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K) array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.
Published: 2016

47. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L
Abstract: BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
Published: 2016

48. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomaeki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Foersti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkaes, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teule, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, van Deurzen, CHM, van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, Garcia-Closas, M, Easton, DF, Antoniou, AC, Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomaeki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Foersti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkaes, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teule, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, van Deurzen, CHM, van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, Garcia-Closas, M, Easton, DF, and Antoniou, AC
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Published: 2016

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

Author: Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, J-Y, Claes, KBM, Cook, LS, Cox, A, Cramer, DW, Cross, SS, Cybulski, C, Czene, K, Daly, MB, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, Dennis, J, Devilee, P, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Doerk, T, Dumont, M, Ehrencrona, H, Ejlertsen, B, Ellis, S, Engel, C, Lee, E, Evans, DG, Fasching, PA, Feliubadalo, L, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Foretova, L, Fostira, F, Foulkes, WD, Fridley, BL, Friedman, E, Frost, D, Gambino, G, Ganz, PA, Garber, J, Garcia-Closas, M, Gentry-Maharaj, A, Ghoussaini, M, Giles, GG, Glasspool, R, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Goode, EL, Goodman, MT, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hallberg, E, Hamann, U, Hansen, TVO, Harrington, PA, Hartman, M, Hassan, N, Healey, S, Heitz, F, Herzog, J, Hogdall, E, Hogdall, CK, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Hulick, PJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jensen, A, John, EM, Johnson, N, Kabisch, M, Kang, D, Kapuscinski, M, Karlan, BY, Khan, S, Kiemeney, LA, Kjaer, SK, Knight, JA, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kupryjanczyk, J, Kwong, A, de la Hoya, M, Laitman, Y, Lambrechts, D, Le, N, De Leeneer, K, Lester, J, Levine, DA, Li, J, Lindblom, A, Long, J, Lophatananon, A, Loud, JT, Lu, K, Lubinski, J, Mannermaa, A, Manoukian, S, Le Marchand, L, Margolin, S, Marme, F, Massuger, LFAG, Matsuo, K, Mazoyer, S, McGuffog, L, McLean, C, McNeish, I, Meindl, A, Menon, U, Mensenkamp, AR, Milne, RL, Montagna, M, Moysich, KB, Muir, K, Mulligan, AM, Nathanson, KL, Ness, RB, Neuhausen, SL, Nevanlinna, H, Nord, S, Nussbaum, RL, Odunsi, K, Offit, K, Olah, E, Olopade, OI, Olson, JE, Olswold, C, O'Malley, D, Orlow, I, Orr, N, Osorio, A, Park, SK, Pearce, CL, Pejovic, T, Peterlongo, P, Pfeiler, G, Phelan, CM, Poole, EM, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rhenius, V, Rhiem, K, Risch, HA, Rodriguez, G, Rossing, MA, Rudolph, A, Salvesen, HB, Sangrajrang, S, Sawyer, EJ, Schildkraut, JM, Schmidt, MK, Schmutzler, RK, Sellers, TA, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Sieh, W, Singer, CF, Sinilnikova, OM, Slager, S, Song, H, Soucy, P, Southey, MC, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Sutter, C, Swerdlow, A, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Tseng, C-C, Tung, N, Tworoger, SS, Vachon, C, van den Ouweland, AMW, van Doorn, HC, van Rensburg, EJ, Van't Veer, LJ, Vanderstichele, A, Vergote, I, Vijai, J, Wang, Q, Wang-Gohrke, S, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wildiers, H, Winqvist, R, Wu, AH, Yannoukakos, D, Yoon, S-Y, Yu, J-C, Zheng, W, Zheng, Y, Khanna, KK, Simard, J, Monteiro, AN, French, JD, Couch, FJ, Freedman, ML, Easton, DF, Dunning, AM, Pharoah, PD, Edwards, SL, Chenevix-Trench, G, Antoniou, AC, Gayther, SA, Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, J-Y, Claes, KBM, Cook, LS, Cox, A, Cramer, DW, Cross, SS, Cybulski, C, Czene, K, Daly, MB, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, Dennis, J, Devilee, P, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Doerk, T, Dumont, M, Ehrencrona, H, Ejlertsen, B, Ellis, S, Engel, C, Lee, E, Evans, DG, Fasching, PA, Feliubadalo, L, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Foretova, L, Fostira, F, Foulkes, WD, Fridley, BL, Friedman, E, Frost, D, Gambino, G, Ganz, PA, Garber, J, Garcia-Closas, M, Gentry-Maharaj, A, Ghoussaini, M, Giles, GG, Glasspool, R, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Goode, EL, Goodman, MT, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hallberg, E, Hamann, U, Hansen, TVO, Harrington, PA, Hartman, M, Hassan, N, Healey, S, Heitz, F, Herzog, J, Hogdall, E, Hogdall, CK, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Hulick, PJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jensen, A, John, EM, Johnson, N, Kabisch, M, Kang, D, Kapuscinski, M, Karlan, BY, Khan, S, Kiemeney, LA, Kjaer, SK, Knight, JA, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kupryjanczyk, J, Kwong, A, de la Hoya, M, Laitman, Y, Lambrechts, D, Le, N, De Leeneer, K, Lester, J, Levine, DA, Li, J, Lindblom, A, Long, J, Lophatananon, A, Loud, JT, Lu, K, Lubinski, J, Mannermaa, A, Manoukian, S, Le Marchand, L, Margolin, S, Marme, F, Massuger, LFAG, Matsuo, K, Mazoyer, S, McGuffog, L, McLean, C, McNeish, I, Meindl, A, Menon, U, Mensenkamp, AR, Milne, RL, Montagna, M, Moysich, KB, Muir, K, Mulligan, AM, Nathanson, KL, Ness, RB, Neuhausen, SL, Nevanlinna, H, Nord, S, Nussbaum, RL, Odunsi, K, Offit, K, Olah, E, Olopade, OI, Olson, JE, Olswold, C, O'Malley, D, Orlow, I, Orr, N, Osorio, A, Park, SK, Pearce, CL, Pejovic, T, Peterlongo, P, Pfeiler, G, Phelan, CM, Poole, EM, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rhenius, V, Rhiem, K, Risch, HA, Rodriguez, G, Rossing, MA, Rudolph, A, Salvesen, HB, Sangrajrang, S, Sawyer, EJ, Schildkraut, JM, Schmidt, MK, Schmutzler, RK, Sellers, TA, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Sieh, W, Singer, CF, Sinilnikova, OM, Slager, S, Song, H, Soucy, P, Southey, MC, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Sutter, C, Swerdlow, A, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Tseng, C-C, Tung, N, Tworoger, SS, Vachon, C, van den Ouweland, AMW, van Doorn, HC, van Rensburg, EJ, Van't Veer, LJ, Vanderstichele, A, Vergote, I, Vijai, J, Wang, Q, Wang-Gohrke, S, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wildiers, H, Winqvist, R, Wu, AH, Yannoukakos, D, Yoon, S-Y, Yu, J-C, Zheng, W, Zheng, Y, Khanna, KK, Simard, J, Monteiro, AN, French, JD, Couch, FJ, Freedman, ML, Easton, DF, Dunning, AM, Pharoah, PD, Edwards, SL, Chenevix-Trench, G, Antoniou, AC, and Gayther, SA
Abstract: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Published: 2016

50. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Zeng, C, Guo, X, Long, J, Kuchenbaecker, KB, Droit, A, Michailidou, K, Ghoussaini, M, Kar, S, Freeman, A, Hopper, JL, Milne, RL, Bolla, MK, Wang, Q, Dennis, J, Agata, S, Ahmed, S, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Arun, BK, Arver, B, Bacot, F, Barrowdale, D, Baynes, C, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, WJ, Bogdanova, NV, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Carpenter, J, Chang-Claude, J, Choi, J-Y, Claes, KBM, Clarke, C, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Devilee, P, Diez, O, Domchek, SM, Doody, M, Dorfling, CM, Doerk, T, dos-Santos-Silva, I, Dumont, M, Dwek, M, Dworniczak, B, Egan, K, Eilber, U, Einbeigi, Z, Ejlertsen, B, Ellis, S, Frost, D, Lalloo, F, Fasching, PA, Figueroa, J, Flyger, H, Friedlander, M, Friedman, E, Gambino, G, Gao, Y-T, Garber, J, Garcia-Closas, M, Gehrig, A, Damiola, F, Lesueur, F, Mazoyer, S, Stoppa-Lyonnet, D, Giles, GG, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Haiman, CA, Hallberg, E, Hamann, U, Hansen, TVO, Hart, S, Hartikainen, JM, Hartman, M, Hassan, N, Healey, S, Hogervorst, FBL, Verhoef, S, Hendricks, CB, Hillemanns, P, Hollestelle, A, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Beauparlant, CJ, Jones, M, Kabisch, M, Kang, D, Karlan, BY, Kauppila, S, Kerin, MJ, Khan, S, Khusnutdinova, E, Knight, JA, Konstantopoulou, I, Kraft, P, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Le Marchand, L, Lee, CN, Lee, MH, Lester, J, Li, J, Liljegren, A, Lindblom, A, Lophatananon, A, Lubinski, J, Mai, PL, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McGuffog, L, Meindl, A, Menegaux, F, Montagna, M, Muir, K, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Nord, S, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olswold, C, Osorio, A, Papi, L, Park-Simon, T-W, Paulsson-Karlsson, Y, Peeters, S, Peissel, B, Peterlongo, P, Peto, J, Pfeiler, G, Phelan, CM, Presneau, N, Radice, P, Rahman, N, Ramus, SJ, Rashid, MU, Rennert, G, Rhiem, K, Rudolph, A, Salani, R, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schuermann, P, Seynaeve, C, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Sigurdson, A, Singer, CF, Slager, S, Soucy, P, Southey, M, Steinemann, D, Swerdlow, A, Szabo, CI, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, MB, Tessier, DC, Teule, A, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Tung, N, Turnbull, C, van den Ouweland, AMW, van Rensburg, EJ, ven den Berg, D, Vijai, J, Wang-Gohrke, S, Weitzel, JN, Whittemore, AS, Winqvist, R, Wong, TY, Wu, AH, Yannoukakos, D, Yu, J-C, Pharoah, PDP, Hall, P, Chenevix-Trench, G, Dunning, AM, Simard, J, Couch, FJ, Antoniou, AC, Easton, DF, Zheng, W, Zeng, C, Guo, X, Long, J, Kuchenbaecker, KB, Droit, A, Michailidou, K, Ghoussaini, M, Kar, S, Freeman, A, Hopper, JL, Milne, RL, Bolla, MK, Wang, Q, Dennis, J, Agata, S, Ahmed, S, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Arun, BK, Arver, B, Bacot, F, Barrowdale, D, Baynes, C, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, WJ, Bogdanova, NV, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Carpenter, J, Chang-Claude, J, Choi, J-Y, Claes, KBM, Clarke, C, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Devilee, P, Diez, O, Domchek, SM, Doody, M, Dorfling, CM, Doerk, T, dos-Santos-Silva, I, Dumont, M, Dwek, M, Dworniczak, B, Egan, K, Eilber, U, Einbeigi, Z, Ejlertsen, B, Ellis, S, Frost, D, Lalloo, F, Fasching, PA, Figueroa, J, Flyger, H, Friedlander, M, Friedman, E, Gambino, G, Gao, Y-T, Garber, J, Garcia-Closas, M, Gehrig, A, Damiola, F, Lesueur, F, Mazoyer, S, Stoppa-Lyonnet, D, Giles, GG, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Haiman, CA, Hallberg, E, Hamann, U, Hansen, TVO, Hart, S, Hartikainen, JM, Hartman, M, Hassan, N, Healey, S, Hogervorst, FBL, Verhoef, S, Hendricks, CB, Hillemanns, P, Hollestelle, A, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Beauparlant, CJ, Jones, M, Kabisch, M, Kang, D, Karlan, BY, Kauppila, S, Kerin, MJ, Khan, S, Khusnutdinova, E, Knight, JA, Konstantopoulou, I, Kraft, P, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Le Marchand, L, Lee, CN, Lee, MH, Lester, J, Li, J, Liljegren, A, Lindblom, A, Lophatananon, A, Lubinski, J, Mai, PL, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McGuffog, L, Meindl, A, Menegaux, F, Montagna, M, Muir, K, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Nord, S, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olswold, C, Osorio, A, Papi, L, Park-Simon, T-W, Paulsson-Karlsson, Y, Peeters, S, Peissel, B, Peterlongo, P, Peto, J, Pfeiler, G, Phelan, CM, Presneau, N, Radice, P, Rahman, N, Ramus, SJ, Rashid, MU, Rennert, G, Rhiem, K, Rudolph, A, Salani, R, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schuermann, P, Seynaeve, C, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Sigurdson, A, Singer, CF, Slager, S, Soucy, P, Southey, M, Steinemann, D, Swerdlow, A, Szabo, CI, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, MB, Tessier, DC, Teule, A, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Tung, N, Turnbull, C, van den Ouweland, AMW, van Rensburg, EJ, ven den Berg, D, Vijai, J, Wang-Gohrke, S, Weitzel, JN, Whittemore, AS, Winqvist, R, Wong, TY, Wu, AH, Yannoukakos, D, Yu, J-C, Pharoah, PDP, Hall, P, Chenevix-Trench, G, Dunning, AM, Simard, J, Couch, FJ, Antoniou, AC, Easton, DF, and Zheng, W
Abstract: BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This
Published: 2016

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