Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers / Peterlongo P; Chang-Claude J; Moysich KB; Rudolph A; Schmutzler RK; Simard J; Soucy P; Eeles RA; Easton DF; Hamann U; Wilkening S; Chen B; Rookus MA; Schmidt MK; van der Baan FH; Spurdle AB; Walker LC; Lose F; Maia AT; Montagna M; Matricardi L; Lubinski J; Jakubowska A; Gomez-Garcia EB; Olopade OI; Nussbaum RL; Nathanson KL; Domchek SM; Rebbeck TR; Arun BK; Karlan BY; Orsulic S; Lester J; Chung WK; Miron A; Southey MC; Goldgar DE; Buys SS; Janavicius R; Dorfling CM; van Rensburg EJ; Ding YC; Neuhausen SL; Hansen TV; Gerdes AM; Ejlertsen B; Jønson L; Osorio A; Martinez-Bouzas C; Benitez J; Conway EE; Blazer KR; Weitzel JN; Manoukian S; Peissel B; Zaffaroni D; Scuvera G; Barile M; Ficarazzi F; Mariette F; Fortuzzi S; Viel A; Giannini G; Papi L; Martayan A; Tibiletti MG; Radice P; Vratimos A; Fostira F; Garber JE; Donaldson A; Brewer C; Foo C; Evans DG; Frost D; Eccles D; Brady A; Cook J; Tischkowitz M; Adlard J; Barwell J; Walker L; Izatt L; Side LE; Kennedy MJ; Rogers MT; Porteous ME; Morrison PJ; Platte R; Davidson R; Hodgson SV; Ellis S; Cole T; Godwin AK; Claes K; Van Maerken T; Meindl A; Gehrig A; Sutter C; Engel C; Niederacher D; Steinemann D; Plendl H; Kast K; Rhiem K; Ditsch N; Arnold N; Varon-Mateeva R; Wappenschmidt B; Wang-Gohrke S; Bressac-de Paillerets B; Buecher B; Delnatte C; Houdayer C; Stoppa-Lyonnet D; Damiola F; Coupier I; Barjhoux L; Venat-Bouvet L; Golmard L; Boutry-Kryza N; Sinilnikova OM; Caron O; Pujol P; Mazoyer S; Belotti M; Piedmonte M; Friedlander ML; Rodriguez GC; Copeland LJ; de la Hoya M; Perez Segura P; Nevanlinna H; Aittomäki K; van Os TA; Meijers-Heijboer HE; Van der Hout AH; Vreeswijk MP; Hoogerbrugge N; Ausems MG; Van Doorn HC; Collée JM; Olah E; Díez O; Blanco I; Lazaro C; Brunet J; Feliubadaló L; Cybulski C; Gronwald J; Durda K; Jaworska-Bieniek K; Sukiennicki G; Arason A; Chiquette J; Teixeira MR; Olswold C; Couch FJ; Lindor NM; Wang X; Szabo CI; Offit K; Corines M; Jacobs L; Robson M; Zhang L; Joseph V; Berger A; Singer CF; Rappaport C; Geschwantler Kaulich D; Pfeiler G; Tea MK; Phelan CM; Greene MH; Mai PL; Rennert G; Mulligan AM; Glendon G; Tchatchou S; Andrulis IL; Toland AE; Bojesen A; Pedersen IS; Thomassen M; Jensen UB; Laitman Y; Rantala J; von Wachenfeldt A; Ehrencrona H; Stenmark Askmalm M; Borg A; Kuchenbaecker KB; McGuffog L; Barrowdale D; Healey S; Lee A; Pharoah PD; Chenevix-Trench G On Behalf Of Aocs Mamagement Group; Antoniou AC; Friedman E.. - In: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION. - ISSN 1055-9965. - ELETTRONICO. - 24:(2015), pp. 308-316. [10.1158/1055-9965.EPI-14-0532]
Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
PAPI, LAURA;
2015
Abstract
Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
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