Abstract Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers / Ramus SJ; Antoniou AC; Kuchenbaecker KB; Soucy P; Beesley J; Chen X; McGuffog L; Sinilnikova OM; Healey S; Barrowdale D; Lee A; Thomassen M; Gerdes AM; Kruse TA; Jensen UB; Skytte AB; Caligo MA; Liljegren A; Lindblom A; Olsson H; Kristoffersson U; Stenmark-Askmalm M; Melin B; SWE-BRCA.; Domchek SM; Nathanson KL; Rebbeck TR; Jakubowska A; Lubinski J; Jaworska K; Durda K; Złowocka E; Gronwald J; Huzarski T; Byrski T; Cybulski C; Toloczko-Grabarek A; Osorio A; Benitez J; Duran M; Tejada MI; Hamann U; Rookus M; van Leeuwen FE; Aalfs CM; Meijers-Heijboer HE; van Asperen CJ; van Roozendaal KE; Hoogerbrugge N; Collée JM; Kriege M; van der Luijt RB; HEBON.; EMBRACE.; Peock S; Frost D; Ellis SD; Platte R; Fineberg E; Evans DG; Lalloo F; Jacobs C; Eeles R; Adlard J; Davidson R; Eccles D; Cole T; Cook J; Paterson J; Douglas F; Brewer C; Hodgson S; Morrison PJ; Walker L; Porteous ME; Kennedy MJ; Pathak H; Godwin AK; Stoppa-Lyonnet D; Caux-Moncoutier V; de Pauw A; Gauthier-Villars M; Mazoyer S; Léoné M; Calender A; Lasset C; Bonadona V; Hardouin A; Berthet P; Bignon YJ; Uhrhammer N; Faivre L; Loustalot C; GEMO.; Buys S; Daly M; Miron A; Terry MB; Chung WK; John EM; Southey M; Goldgar D; Singer CF; Tea MK; Pfeiler G; Fink-Retter A; Hansen Tv; Ejlertsen B; Johannsson OT; Offit K; Kirchhoff T; Gaudet MM; Vijai J; Robson M; Piedmonte M; Phillips KA; Van Le L; Hoffman JS; Ewart Toland A; Montagna M; Tognazzo S; Imyanitov E; Issacs C; Janavicius R; Lazaro C; Blanco I; Tornero E; Navarro M; Moysich KB; Karlan BY; Gross J; Olah E; Vaszko T; Teo SH; Ganz PA; Beattie MS; Dorfling CM; van Rensburg EJ; Diez O; Kwong A; Schmutzler RK; Wappenschmidt B; Engel C; Meindl A; Ditsch N; Arnold N; Heidemann S; Niederacher D; Preisler-Adams S; Gadzicki D; Varon-Mateeva R; Deissler H; Gehrig A; Sutter C; Kast K; Fiebig B; Schäfer D; Caldes T; de la Hoya M; Nevanlinna H; Aittomäki K; Plante M; Spurdle AB; kConFab.; Neuhausen SL; Ding YC; Wang X; Lindor N; Fredericksen Z; Pankratz VS; Peterlongo P; Manoukian S; Peissel B; Zaffaroni D; Bonanni B; Bernard L; Dolcetti R; Papi L; Ottini L; Radice P; Greene MH; Mai PL; Andrulis IL; Glendon G; Ozcelik H; OCGN.; Pharoah PD; Gayther SA; Simard J; Easton DF; Couch. - In: HUMAN MUTATION. - ISSN 1059-7794. - STAMPA. - 33:(2012), pp. 690-702. [10.1002/humu.22025]

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

PAPI, LAURA;
2012

Abstract

Abstract Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
2012
33
690
702
Ramus SJ; Antoniou AC; Kuchenbaecker KB; Soucy P; Beesley J; Chen X; McGuffog L; Sinilnikova OM; Healey S; Barrowdale D; Lee A; Thomassen M; Gerdes AM; Kruse TA; Jensen UB; Skytte AB; Caligo MA; Liljegren A; Lindblom A; Olsson H; Kristoffersson U; Stenmark-Askmalm M; Melin B; SWE-BRCA.; Domchek SM; Nathanson KL; Rebbeck TR; Jakubowska A; Lubinski J; Jaworska K; Durda K; Złowocka E; Gronwald J; Huzarski T; Byrski T; Cybulski C; Toloczko-Grabarek A; Osorio A; Benitez J; Duran M; Tejada MI; Hamann U; Rookus M; van Leeuwen FE; Aalfs CM; Meijers-Heijboer HE; van Asperen CJ; van Roozendaal KE; Hoogerbrugge N; Collée JM; Kriege M; van der Luijt RB; HEBON.; EMBRACE.; Peock S; Frost D; Ellis SD; Platte R; Fineberg E; Evans DG; Lalloo F; Jacobs C; Eeles R; Adlard J; Davidson R; Eccles D; Cole T; Cook J; Paterson J; Douglas F; Brewer C; Hodgson S; Morrison PJ; Walker L; Porteous ME; Kennedy MJ; Pathak H; Godwin AK; Stoppa-Lyonnet D; Caux-Moncoutier V; de Pauw A; Gauthier-Villars M; Mazoyer S; Léoné M; Calender A; Lasset C; Bonadona V; Hardouin A; Berthet P; Bignon YJ; Uhrhammer N; Faivre L; Loustalot C; GEMO.; Buys S; Daly M; Miron A; Terry MB; Chung WK; John EM; Southey M; Goldgar D; Singer CF; Tea MK; Pfeiler G; Fink-Retter A; Hansen Tv; Ejlertsen B; Johannsson OT; Offit K; Kirchhoff T; Gaudet MM; Vijai J; Robson M; Piedmonte M; Phillips KA; Van Le L; Hoffman JS; Ewart Toland A; Montagna M; Tognazzo S; Imyanitov E; Issacs C; Janavicius R; Lazaro C; Blanco I; Tornero E; Navarro M; Moysich KB; Karlan BY; Gross J; Olah E; Vaszko T; Teo SH; Ganz PA; Beattie MS; Dorfling CM; van Rensburg EJ; Diez O; Kwong A; Schmutzler RK; Wappenschmidt B; Engel C; Meindl A; Ditsch N; Arnold N; Heidemann S; Niederacher D; Preisler-Adams S; Gadzicki D; Varon-Mateeva R; Deissler H; Gehrig A; Sutter C; Kast K; Fiebig B; Schäfer D; Caldes T; de la Hoya M; Nevanlinna H; Aittomäki K; Plante M; Spurdle AB; kConFab.; Neuhausen SL; Ding YC; Wang X; Lindor N; Fredericksen Z; Pankratz VS; Peterlongo P; Manoukian S; Peissel B; Zaffaroni D; Bonanni B; Bernard L; Dolcetti R; Papi L; Ottini L; Radice P; Greene MH; Mai PL; Andrulis IL; Glendon G; Ozcelik H; OCGN.; Pharoah PD; Gayther SA; Simard J; Easton DF; Couch
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