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    PloS one. 2016 Jul 27. doi: 10.1371/journal.pone.0158801. pii: PONE-D-16-10426
    Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
    Vigorito E1,  Kuchenbaecker KB2,  Beesley J3,  Adlard J4,  Agnarsson BA5,  Andrulis IL6,  Arun BK7,  Barjhoux L8,  Belotti M9,  Benitez J10,  Berger A11,  Bojesen A12,  Bonanni B13,  Brewer C14,  Caldes T15,  Caligo MA16,  Campbell I17,  Chan SB18,  Claes KB19,  Cohn DE20,  Cook J21,  Daly MB22,  Damiola F23,  Davidson R24,  Pauw A25,  Delnatte C26,  Diez O27,  Domchek SM28,  Dumont M29,  Durda K30,  Dworniczak B31,  Easton DF32,  Eccles D33,  Edwinsdotter Ardnor C34,  Eeles R35,  Ejlertsen B36,  Ellis S37,  Evans DG38,  Feliubadalo L39,  Fostira F40,  Foulkes WD41,  Friedman E42,  Frost D43,  Gaddam P44,  Ganz PA45,  Garber J46,  Garcia-Barberan V47,  Gauthier-Villars M48,  Gehrig A49,  Gerdes AM50,  Giraud S51,  Godwin AK52,  Goldgar DE53,  Hake CR54,  Hansen TV55,  Healey S56,  Hodgson S57,  Hogervorst FB58,  Houdayer C59,  Hulick PJ60,  Imyanitov EN61,  Isaacs C62,  Izatt L63,  Izquierdo A64,  Jacobs L65,  Jakubowska A66,  Janavicius R67,  Jaworska-Bieniek K68,  Jensen UB69,  John EM70,  Vijai J71,  Karlan BY72,  Kast K73,  Investigators K74,  Khan S75,  Kwong A76,  Laitman Y77,  Lester J78,  Lesueur F79,  Liljegren A80,  Lubinski J81,  Mai PL82,  Manoukian S83,  Mazoyer S84,  Meindl A85,  Mensenkamp AR86,  Montagna M87,  Nathanson KL88,  Neuhausen SL89,  Nevanlinna H90,  Niederacher D91,  Olah E92,  Olopade OI93,  Ong KR94,  Osorio A95,  Park SK96,  Paulsson-Karlsson Y97,  Pedersen IS98,  Peissel B99,  Peterlongo P100,  Pfeiler G101,  Phelan CM102,  Piedmonte M103,  Poppe B104,  Pujana MA105,  Radice P106,  Rennert G107,  Rodriguez GC108,  Rookus MA109,  Ross EA110,  Schmutzler RK111,  Simard J112,  Singer CF113,  Slavin TP114,  Soucy P115,  Southey M116,  Steinemann D117,  Stoppa-Lyonnet D118,  Sukiennicki G119,  Sutter C120,  Szabo CI121,  Tea MK122,  Teixeira MR123,  Teo SH124,  Terry MB125,  Thomassen M126,  Tibiletti MG127,  Tihomirova L128,  Tognazzo S129,  van Rensburg EJ130,  Varesco L131,  Varon-Mateeva R132,  Vratimos A133,  Weitzel JN134,  McGuffog L135,  Kirk J136,  Toland AE137,  Hamann U138,  Lindor N139,  Ramus SJ140,  Greene MH141,  Couch FJ142,  Offit K143,  Pharoah PD144,  Chenevix-Trench G145,  Antoniou AC146
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    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.


    Publikations ID: 27463617
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