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

Couch, F, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, K, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, M, Dicks, E, Kosel, M, Healey, S, Sinilnikova, O, Lee, A, Bacot, F, Vincent, D, Hogervorst, F, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Investigators, k, Radice, P, Schmutzler, R, Domchek, S, Piedmonte, M, Singer, C, Friedman, E, Thomassen, M, Hansen, T, Neuhausen, S, Szabo, C, Blanco, I, Greene, M, Karlan, B, Garber, J, Phelan, C, Weitzel, J, Montagna, M, Olah, E, Andrulis, I, Godwin, A, Yannoukakos, D, Goldgar, D, Caldes, T, Nevanlinna, H, Osorio, A, Terry, M, Daly, M, van Rensburg, E, Hamann, U, Ramus, S, Ewart Toland, A, Caligo, M, Olopade, O, Tung, N, Claes, K, Beattie, M, Southey, M, Imyanitov, E, Tischkowitz, M, Janavicius, R, John, E, Kwong, A, Diez, O, Balmaña, J, Barkardottir, R, Arun, A, Rennert, G, Teo, H, Ganz, P, Campbell, I, van der Hout, A, van Deurzen, C, Seynaeve, C, Gómez Garcia, E, van Leeuwen, F, Meijers-Heijboer, H, Gills, J, Ausems, M, Blok, M, Ligtenberg, M, Rookus, M, Devilee, P, Verhoef, S, van Os, T, Wijneb, J, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, D, Izatt, L, Eeles, R, Adlard, J, Eccles, D, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, P, Side, L, Donaldson, A, Houghton, C, Rogers, Mark, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Léone, M, Pujol, P, Mazoyer, S, Bignon, Y, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, A, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, M, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, B, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, K, Rebbeck, T, Blank, S, Cohn, D, Rodriguez, G, Small, L, Friedlander, M, Bae-Jump, V, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M, Lindor, N, Kaufman, B, Shimon Paluch, S, Laitman, Y, Skytte, A, Gerdes, A, Pedersen, I, Moeller, S, Kruse, T, Jensen, U, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, A, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, F, Jønson, L, Andersen, M, Ding, Y, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Pujana, M, Mai, P, Loud, J, Walsh, C, Lester, J, Orsulic, S, Narod, S, Herzog, J, Sand, S, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, A, Buys, S, Romero, A, de la Hoya, M, Aittomäki, K, Muranen, T, Duran, M, Chung, W, Lasa, A, Dorfling, C, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, S, Sokolenko, A, Chiquette, J, Tihomirova, L, Friebel, T, Agnarsson, B, Lu, K, Lejbkowicz, F, James, P, Hall, P, Dunning, A, Tessier, D, Cunningham, J, Slager, S, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, V, Offit, K, Easton, D, Chenevix-Trench, G and Antoniou, A. 2013. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genetics 9 (3) , e1003212. 10.1371/journal.pgen.1003212

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Abstract

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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: BRCA1 Protein/genetics*;BRCA2 Protein/genetics;Breast Neoplasms/genetics*;Breast Neoplasms/pathology;Female;Genetic Predisposition to Disease;Genome-Wide Association Study*;Genotype;Heterozygote;Humans;Middle Aged;Mutation; Ovarian Neoplasms/genetics*;Ovarian Neoplasms/pathology; Polymorphism, Single Nucleotide;Prognosis;Risk Factors
Publisher: Public Library of Science
ISSN: 1553-7390
Date of First Compliant Deposit: 9 April 2018
Last Modified: 10 Apr 2018 19:54
URI: http://orca.cf.ac.uk/id/eprint/110337

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