Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
Creators: name: Couch, Fergus J.
name: Wang, Xianshu
name: McGuffog, Lesley
name: Lee, Andrew
name: Olswold, Curtis
name: Kuchenbaecker, Karoline B.
name: Soucy, Penny
name: Fredericksen, Zachary
name: Barrowdale, Daniel
name: Dennis, Joe
name: Gaudet, Mia M.
name: Dicks, Ed
name: Kosel, Matthew
name: Healey, Sue
name: Sinilnikova, Olga M.
name: Lee, Adam
name: Bacot, François
name: Vincent, Daniel
name: Hogervorst, Frans B. L.
name: Peock, Susan
name: Stoppa-Lyonnet, Dominique
name: Jakubowska, Anna
name: Radice, Paolo
name: Schmutzler, Rita Katharina
name: Domchek, Susan M.
name: Piedmonte, Marion
name: Singer, Christian F.
name: Friedman, Eitan
name: Thomassen, Mads
name: Hansen, Thomas V. O.
name: Neuhausen, Susan L.
name: Szabo, Csilla I.
name: Blanco, Ignacio
name: Greene, Mark H.
name: Karlan, Beth Y.
name: Garber, Judy
name: Phelan, Catherine M.
name: Weitzel, Jeffrey N.
name: Montagna, Marco
name: Olah, Edith
name: Andrulis, Irene L.
name: Godwin, Andrew K.
name: Yannoukakos, Drakoulis
name: Goldgar, David E.
name: Caldes, Trinidad
name: Nevanlinna, Heli
name: Osorio, Ana
name: Terry, Mary Beth
name: Daly, Mary B.
name: Van Rensburg, Elizabeth J.
name: Hamann, Ute
name: Ramus, Susan J.
name: Toland, Amanda Ewart
name: Caligo, Maria A.
name: Olopade, Olufunmilayo I.
name: Tung, Nadine
name: Claes, Kathleen
name: Beattie, Mary S.
name: Southey, Melissa C.
name: Imyanitov, Evgeny N.
name: Tischkowitz, Marc
name: Janavicius, Ramunas
name: John, Esther M.
name: Kwong, Ava
name: Diez, Orland
name: Balmaña, Judith
name: Barkardottir, Rosa B.
name: Arun, Banu K.
name: Rennert, Gad
name: Teo, Soo-Hwang
name: Ganz, Patricia A.
name: Campbell, Ian
name: Van Der Hout, Annemarie H.
name: Van Deurzen, Carolien H. M.
name: Seynaeve, Caroline
name: Gómez Garcia, Encarna B.
name: Van Leeuwen, Flora E.
name: Meijers-Heijboer, Hanne E. J.
name: Gille, Johannes J. P.
name: Ausems, Margaret G. E. M.
name: Blok, Marinus J.
name: Ligtenberg, Marjolijn J. L.
name: Rookus, Matti A.
name: Devilee, Peter
name: Verhoef, Senno
name: Van Os, Theo A. M.
name: Wijnen, Juul T.
name: Frost, Debra
name: Ellis, Steve
name: Fineberg, Elena
name: Izatt, Louise
name: Platte, Radka
name: Evans, D. Gareth
name: Eeles, Rosalind A.
name: Adlard, Julian
name: Eccles, Diana M.
name: Cook, Jackie
name: Brewer, Carole
name: Douglas, Fiona
name: Hodgson, Shirley
name: Murray, Alex
name: Morrison, Patrick J.
name: Side, Lucy E.
name: Gregory, Helen
name: Donaldson, Alan
name: Dorkins, Huw
name: Houghton, Catherine
name: Rogers, Mark T.
name: McCann, Emma
name: Eason, Jacqueline
name: Calender, Alain
name: Hardouin, Agnès
name: Berthet, Pascaline
name: Delnatte, Capucine
name: Nogues, Catherine
name: Lasset, Christine
name: Houdayer, Claude
name: Leroux, Dominique
name: Rouleau, Etienne
name: Prieur, Fabienne
name: Damiola, Francesca
name: Sobol, Hagay
name: Coupier, Isabelle
name: Venat-Bouvet, Laurence
name: Castera, Laurent
name: Gauthier-Villars, Marion
name: Léoné, Mélanie
name: Pujol, Pascal
name: Mazoyer, Sylvie
name: Bignon, Yves-Jean
name: , GEMO Study Collaborators
name: Złowocka-Perłowska, Elżbieta
name: Gronwald, Jacek
name: Lubinski, Jan
name: Durda, Katarzyna
name: Jaworska, Katarzyna
name: Huzarski, Tomasz
name: Spurdle, Amanda B.
name: Viel, Alessandra
name: Peissel, Bernard
name: Bonanni, Bernardo
name: Melloni, Giulia
name: Ottini, Laura
name: Papi, Laura
name: Varesco, Liliana
name: Tibiletti, Maria Grazia
name: Peterlongo, Paolo
name: Volorio, Sara
name: Manoukian, Siranoush
name: Pensotti, Valeria
name: Arnold, Norbert
name: Engel, Chrisoph
name: Deissler, Helmut
name: Gadzicki, Dorothea
name: Gehrig, Andrea
name: Kast, Karin
name: Rhiem, Kerstin
name: Meindl, Alfons
name: Niederacher, Dieter
name: Ditsch, Nina
name: Plendl, Hansjoerg
name: Preisler-Adams, Sabine
name: Engert, Stefanie
name: Sutter, Christian
name: Varon-Mateeva, Raymonda
name: Wappenschmidt, Barbara
name: Weber, Bernhard H. F.
name: Arver, Brita
name: Stenmark-Askmalm, Marie
name: Loman, Niklas
name: Rosenquist, Richard
name: Einbeigi, Zakaria
name: Nathanson, Katherine L.
name: Rebbeck, Timothy R.
name: Blank, Stephanie V.
name: Cohn, David E.
name: Friedlander, Michael
name: Small, Laurie
name: Rodriguez, Gustavo C.
name: Bae-Jump, Victoria L.
name: Fink-Retter, Anneliese
name: Rappaport, Christine
name: Gschwantler-Kaulich, Daphne
name: Pfeiler, Georg
name: Tea, Muy-Kheng
name: Lindor, Noralane M.
name: Kaufman, Bella
name: Paluch, Shani Shimon
name: Skytte, Anne-Bine
name: Laitman, Yael
name: Kruse, Torben A.
name: Pedersen, Inge Sokilde
name: Gerdes, Anne-Marie
name: Moeller, Sanne Traasdahl
name: Jensen, Uffe Birk
name: Vijai, Joseph
name: Sarrel, Kara
name: Robson, Mark
name: Kauff, Noah
name: Mulligan, Anna Marie
name: Glendon, Gord
name: Ejlertsen, Bent
name: Ozcelik, Hilmi
name: Nielsen, Finn C.
name: Jønson, Lars
name: Andersen, Mette K.
name: Ding, Yuan Chun
name: Steele, Linda
name: Foretova, Lenka
name: Lazaro, Conxi
name: Teule, Alex
name: Brunet, Joan
name: Pujana, Miquel Angel
name: Mai, Phuong L.
name: Loud, Jennifer T.
name: Walsh, Christine
name: Lester, Jenny
name: Orsulic, Sandra
name: Narod, Steven A.
name: Herzog, Josef
name: Tognazzo, Silvia
name: Sand, Sharon R.
name: Weaver, Joellen
name: Agata, Simona
name: Vaszko, Tibor
name: Stavropoulou, Alexandra V.
name: Buys, Saundra S.
name: Romero, Atocha
name: De La Hoya, Miguel
name: Aittomäki, Kristiina
name: Muranen, Taru A.
name: Duran, Mercedes
name: Chung, Wendy K.
name: Lasa, Adriana
name: Dorfling, Cecilia M.
name: Miron, Alexander
name: , BCFR
name: Benitez, Javier
name: Senter, Leigha
name: Chan, Salina B.
name: Huo, Dezheng
name: Sokolenko, Anna P.
name: Chiquette, Jocelyne
name: Tihomirova, Laima
name: Friebel, Tara M.
name: Agnarsson, Bjarni A.
name: Lu, Karen H.
name: James, Paul A.
name: Lejbkowicz, Flavio
name: Hall, Per
name: Dunning, Alison M.
name: Tessier, Daniel
name: Cunningham, Julie
name: Slager, Susan L.
name: Wang, Chen
name: Hart, Steven
name: Stevens, Kristen
name: Simard, Jacques
name: Pastinen, Tomi
name: Pankratz, Vernon S.
name: Offit, Kenneth
name: Easton, Douglas F.
name: Chenevix-Trench, Georgia
name: Antoniou, Antonis C.
Publisher: name: Columbia University
Year: 2013
Subjects: Ovaries--Cancer--Risk factors
Ovaries--Cancer--Genetic aspects
Breast--Cancer--Genetic aspects
Breast--Cancer--Epidemiology
Breast--Cancer--Risk factors
Epidemiology

description: 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.