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.
Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk / Couch FJ; Wang X; McGuffog L; Lee A; Olswold C; Kuchenbaecker KB; Soucy P; Fredericksen Z; Barrowdale D; Dennis J; Gaudet MM; Dicks E; Kosel M; Healey S; Sinilnikova OM; Lee A; Bacot F; Vincent D; Hogervorst FB; Peock S; Stoppa-Lyonnet D; Jakubowska A; kConFab Investigators; Radice P; Schmutzler RK; SWE-BRCA; Domchek SM; Piedmonte M; Singer CF; Friedman E; Thomassen M; Ontario Cancer Genetics Network; Hansen TV; Neuhausen SL; Szabo CI; Blanco I; Greene MH; Karlan BY; Garber J; Phelan CM; Weitzel JN; Montagna M; Olah E; Andrulis IL; Godwin AK; Yannoukakos D; Goldgar DE; Caldes T; Nevanlinna H; Osorio A; Terry MB; Daly MB; van Rensburg EJ; Hamann U; Ramus SJ; Toland AE; Caligo MA; Olopade OI; Tung N; Claes K; Beattie MS; Southey MC; Imyanitov EN; Tischkowitz M; Janavicius R; John EM; Kwong A; Diez O; Balmaña J; Barkardottir RB; Arun BK; Rennert G; Teo SH; Ganz PA; Campbell I; van der Hout AH; van Deurzen CH; Seynaeve C; Gómez Garcia EB; van Leeuwen FE; Meijers-Heijboer HE; Gille JJ; Ausems MG; Blok MJ; Ligtenberg MJ; Rookus MA; Devilee P; Verhoef S; van Os TA; Wijnen JT; HEBON; EMBRACE; Frost D; Ellis S; Fineberg E; Platte R; Evans DG; Izatt L; Eeles RA; Adlard J; Eccles DM; Cook J; Brewer C; Douglas F; Hodgson S; Morrison PJ; Side LE; Donaldson A; Houghton C; Rogers MT; 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; Léoné M; Pujol P; Mazoyer S; Bignon YJ; GEMO Study Collaborators; Złowocka-Perłowska E; Gronwald J; Lubinski J; Durda K; Jaworska K; Huzarski T; Spurdle AB; Viel A; Peissel B; Bonanni B; Melloni G; Ottini L; Papi L; Varesco L; Tibiletti MG; 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 BH; Arver B; Stenmark-Askmalm M; Loman N; Rosenquist R; Einbeigi Z; Nathanson KL; Rebbeck TR; Blank SV; Cohn DE; Rodriguez GC; Small L; Friedlander M; Bae-Jump VL; Fink-Retter A; Rappaport C; Gschwantler-Kaulich D; Pfeiler G; Tea MK; Lindor NM; Kaufman B; Shimon Paluch S; Laitman Y; Skytte AB; Gerdes AM; Pedersen IS; Moeller ST; Kruse TA; Jensen UB; Vijai J; Sarrel K; Robson M; Kauff N; Mulligan AM; Glendon G; Ozcelik H; Ejlertsen B; Nielsen FC; Jønson L; Andersen MK; Ding YC; Steele L; Foretova L; Teulé A; Lazaro C; Brunet J; Pujana MA; Mai PL; Loud JT; Walsh C; Lester J; Orsulic S; Narod SA; Herzog J; Sand SR; Tognazzo S; Agata S; Vaszko T; Weaver J; Stavropoulou AV; Buys SS; Romero A; de la Hoya M; Aittomäki K; Muranen TA; Duran M; Chung WK; Lasa A; Dorfling CM; Miron A; BCFR; Benitez J; Senter L; Huo D; Chan SB; Sokolenko AP; Chiquette J; Tihomirova L; Friebel TM; Agnarsson BA; Lu KH; Lejbkowicz F; James PA; Hall P; Dunning AM; Tessier D; Cunningham J; Slager SL; Wang C; Hart S; Stevens K; Simard J; Pastinen T; Pankratz VS; Offit K; Easton DF; Chenevix-Trench G; Antoniou AC; CIMBA. - In: PLOS GENETICS. - ISSN 1553-7390. - ELETTRONICO. - 9:(2013), pp. 1-21. [10.1371/journal.pgen.1003212]
Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.
PAPI, LAURA;
2013
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.
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Genome Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk.pdf
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