Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.
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Authors
Couch, Fergus JWang, Xianshu
McGuffog, Lesley
Lee, Andrew
Olswold, Curtis
Kuchenbaecker, Karoline B
Soucy, Penny
Fredericksen, Zachary
Barrowdale, Daniel
Dennis, Joe
Gaudet, Mia M
Simard, Jacques
Pastinen, Tomi
Pankratz, Vernon S
Offit, Kenneth
Easton, Douglas F
Singer, Christian F
Chenevix-Trench, Georgia
Antoniou, Antonis C
Friedman, Eitan
McCann, Emma
Gschwantler-Kaulich, Daphne
Thomassen, Mads
Hansen, Thomas V O
Neuhausen, Susan L
Szabo, Csilla I
Blanco, Ignacio
Greene, Mark H
Karlan, Beth Y
Garber, Judy
Phelan, Catherine M
Weitzel, Jeffrey N
Pfeiler, Georg
Murray, Alex
Montagna, Marco
Olah, Edith
Andrulis, Irene L
Godwin, Andrew K
Yannoukakos, Drakoulis
Goldgar, David E
Caldes, Trinidad
Nevanlinna, Heli
Osorio, Ana
Tea, Muy-Kheng
Terry, Mary Beth
Dicks, Ed
Daly, Mary B
van Rensburg, Elizabeth J
Hamann, Ute
Ramus, Susan J
Toland, Amanda Ewart
Caligo, Maria A
Olopade, Olufunmilayo I
Tung, Nadine
Lindor, Noralane M
Claes, Kathleen
Beattie, Mary S
Calender, Alain
Southey, Melissa C
Imyanitov, Evgeny N
Tischkowitz, Marc
Janavicius, Ramunas
John, Esther M
Kwong, Ava
Diez, Orland
Kaufman, Bella
Balmaña, Judith
Barkardottir, Rosa B
Arun, Banu K
Hardouin, Agnès
Rennert, Gad
Teo, Soo-Hwang
Ganz, Patricia A
Campbell, Ian
van der Hout, Annemarie H
van Deurzen, Carolien H M
Shimon Paluch, Shani
Seynaeve, Caroline
Gómez Garcia, Encarna B
van Leeuwen, Flora E
Meijers-Heijboer, Hanne E J
Berthet, Pascaline
Gille, Johannes J P
Ausems, Margreet G E M
Blok, Marinus J
Ligtenberg, Marjolijn J L
Rookus, Matti A
Laitman, Yael
Devilee, Peter
Verhoef, Senno
van Os, Theo A M
Wijnen, Juul T
Frost, Debra
Delnatte, Capucine
Ellis, Steve
Fineberg, Elena
Platte, Radka
Evans, D Gareth
Skytte, Anne-Bine
Izatt, Louise
Eeles, Rosalind A
Adlard, Julian
Eccles, Diana M
Cook, Jackie
Brewer, Carole
Nogues, Catherine
Douglas, Fiona
Hodgson, Shirley
Lasset, Christine
Gerdes, Anne-Marie
Houdayer, Claude
Leroux, Dominique
Rouleau, Etienne
Prieur, Fabienne
Kosel, Matthew
Damiola, Francesca
Sobol, Hagay
Coupier, Isabelle
Venat-Bouvet, Laurence
Castera, Laurent
Peock, Susan
Gauthier-Villars, Marion
Léoné, Mélanie
Pujol, Pascal
Mazoyer, Sylvie
Bignon, Yves-Jean
Healey, Sue
Złowocka-Perłowska, Elżbieta
Gronwald, Jacek
Lubinski, Jan
Durda, Katarzyna
Morrison, Patrick J
Jaworska, Katarzyna
Huzarski, Tomasz
Spurdle, Amanda B
Viel, Alessandra
Peissel, Bernard
Bonanni, Bernardo
Sinilnikova, Olga M
Melloni, Giulia
Ottini, Laura
Papi, Laura
Pedersen, Inge Sokilde
Varesco, Liliana
Tibiletti, Maria Grazia
Peterlongo, Paolo
Volorio, Sara
Manoukian, Siranoush
Pensotti, Valeria
Arnold, Norbert
Lee, Adam
Engel, Christoph
Deissler, Helmut
Moeller, Sanne Traasdahl
Gadzicki, Dorothea
Gehrig, Andrea
Kast, Karin
Rhiem, Kerstin
Meindl, Alfons
Niederacher, Dieter
Ditsch, Nina
Plendl, Hansjoerg
Bacot, François
Preisler-Adams, Sabine
Kruse, Torben A
Engert, Stefanie
Sutter, Christian
Varon-Mateeva, Raymonda
Wappenschmidt, Barbara
Weber, Bernhard H F
Arver, Brita
Stenmark-Askmalm, Marie
Loman, Niklas
Rosenquist, Richard
Vincent, Daniel
Jensen, Uffe Birk
Einbeigi, Zakaria
Nathanson, Katherine L
Rebbeck, Timothy R
Blank, Stephanie V
Cohn, David E
Rodriguez, Gustavo C
Small, Laurie
Friedlander, Michael
Bae-Jump, Victoria L
Fink-Retter, Anneliese
Vijai, Joseph
Hogervorst, Frans B L
Rappaport, Christine
Sarrel, Kara
Robson, Mark
Kauff, Noah
Mulligan, Anna Marie
Glendon, Gord
Side, Lucy E
Stoppa-Lyonnet, Dominique
Ozcelik, Hilmi
Ejlertsen, Bent
Nielsen, Finn C
Jønson, Lars
Andersen, Mette K
Ding, Yuan Chun
Steele, Linda
Foretova, Lenka
Teulé, Alex
Donaldson, Alan
Lazaro, Conxi
Jakubowska, Anna
Brunet, Joan
Pujana, Miquel Angel
Mai, Phuong L
Loud, Jennifer T
Walsh, Christine
Lester, Jenny
Orsulic, Sandra
Narod, Steven A
Houghton, Catherine
Herzog, Josef
Sand, Sharon R
Radice, Paolo
Tognazzo, Silvia
Agata, Simona
Vaszko, Tibor
Weaver, Joellen
Stavropoulou, Alexandra V
Buys, Saundra S
Romero, Atocha
Rogers, Mark T
de la Hoya, Miguel
Aittomäki, Kristiina
Muranen, Taru A
Schmutzler, Rita Katharina
Duran, Mercedes
Chung, Wendy K
Lasa, Adriana
Dorfling, Cecilia M
Miron, Alexander
Benitez, Javier
Dorkins, Huw
Senter, Leigha
Huo, Dezheng
Chan, Salina B
Sokolenko, Anna P
Domchek, Susan M
Chiquette, Jocelyne
Tihomirova, Laima
Friebel, Tara M
Agnarsson, Bjarni A
Lu, Karen H
Eason, Jacqueline
Lejbkowicz, Flavio
James, Paul A
Hall, Per
Dunning, Alison M
Tessier, Daniel
Piedmonte, Marion
Cunningham, Julie
Slager, Susan L
Wang, Chen
Hart, Steven
Gregory, Helen
Stevens, Kristen
Issue Date
2013
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PLoS Genet. 2013, 9 (3):e1003212Abstract
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.Description
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http://dx.doi.org/10.1371/journal.pgen.1003212Rights
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Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.Couch, Fergus J; Gaudet, Mia M; Antoniou, Antonis C; Ramus, Susan J; Kuchenbaecker, Karoline B; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; Wang, Xianshu; Kirchhoff, Tomas; et al. (2012-04)Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.