Publications

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Author(s): Vigorito E,  Kuchenbaecker KB,  Beesley J,  Adlard J,  Agnarsson BA,  Andrulis IL,  Arun BK,  Barjhoux L,  Belotti M,  Benitez J,  Berger A,  Bojesen A,  Bonanni B,  Brewer C,  Caldes T,  Caligo MA,  Campbell I,  Chan SB,  Claes KB,  Cohn DE,  Cook J,  Daly MB,  Damiola F,  Davidson R,  Pauw Ad,  Delnatte C,  Diez O,  Domchek SM,  Dumont M,  Durda K,  Dworniczak B,  Easton DF,  Eccles D,  Edwinsdotter Ardnor C,  Eeles R,  Ejlertsen B,  Ellis S,  Evans DG,  Feliubadalo L,  Fostira F,  Foulkes WD,  Friedman E,  Frost D,  Gaddam P,  Ganz PA,  Garber J,  Garcia-Barberan V,  Gauthier-Villars M,  Gehrig A,  Gerdes AM,  Giraud S,  Godwin AK,  Goldgar DE,  Hake CR,  Hansen TV,  Healey S,  Hodgson S,  Hogervorst FB,  Houdayer C,  Hulick PJ,  Imyanitov EN,  Isaacs C,  Izatt L,  Izquierdo A,  Jacobs L,  Jakubowska A,  Janavicius R,  Jaworska-Bieniek K,  Jensen UB,  John EM,  Vijai J,  Karlan BY,  Kast K,  KConFab Investigators,  Khan S,  Kwong A,  Laitman Y,  Lester J,  Lesueur F,  Liljegren A,  Lubinski J,  Mai PL,  Manoukian S,  Mazoyer S,  Meindl A,  Mensenkamp AR,  Montagna M,  Nathanson KL,  Neuhausen SL,  Nevanlinna H,  Niederacher D,  Olah E,  Olopade OI,  Ong KR,  Osorio A,  Park SK,  Paulsson-Karlsson Y,  Pedersen IS,  Peissel B,  Peterlongo P,  Pfeiler G,  Phelan CM,  Piedmonte M,  Poppe B,  Pujana MA,  Radice P,  Rennert G,  Rodriguez GC,  Rookus MA,  Ross EA,  Schmutzler RK,  Simard J,  Singer CF,  Slavin TP,  Soucy P,  Southey M,  Steinemann D,  Stoppa-Lyonnet D,  Sukiennicki G,  Sutter C,  Szabo CI,  Tea MK,  Teixeira MR,  Teo SH,  Terry MB,  Thomassen M,  Tibiletti MG,  Tihomirova L,  Tognazzo S,  van Rensburg EJ,  Varesco L,  Varon-Mateeva R,  Vratimos A,  Weitzel JN,  McGuffog L,  Kirk J,  Toland AE,  Hamann U,  Lindor N,  Ramus SJ,  Greene MH,  Couch FJ,  Offit K,  Pharoah PD,  Chenevix-Trench G,  Antoniou AC

Journal: PLoS One

Date: 2016

Major Program(s) or Research Group(s): NCORP

PubMed ID: 27463617

PMC ID: PMC4963094

Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.