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

Ramus, S.J.; Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; ... ; Consortium Investigators Modifiers (2012)

Article / Letter to editor

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.

• All authors: Ramus, S.J.; Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Sinilnikova, O.M.; Healey, S.; Barrowdale, D.; Lee, A.; Thomassen, M.; Gerdes, A.M.; Kruse, T.A.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowocka, E.; Gronwald, J.; Huzarski, T.; Byrski, T.; Cybulski, C.; Toloczko-Grabarek, A.; Osorio, A.; Benitez, J.; Duran, M.; Tejada, M.I.; Hamann, U.; Rookus, M.; Leeuwen, F.E. van; Aalfs, C.M.; Meijers-Heijboer, H.E.J.; Asperen, C.J. van; Roozendaal, K.E.P. van; Hoogerbrugge, N.; Collee, J.M.; Kriege, M.; Luijt, R.B. van der; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; 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, P.J.; Walker, L.; Porteous, M.E.; Kennedy, M.J.; Pathak, H.; Godwin, A.K.; Stoppa-Lyonnet, D.; Caux-Moncoutier, V.; Pauw, A. de; Gauthier-Villars, M.; Mazoyer, S.; Leone, M.; Calender, A.; Lasset, C.; Bonadona, V.; Hardouin, A.; Berthet, P.; Bignon, Y.J.; Uhrhammer, N.; Faivre, L.; Loustalot, C.; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.K.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Tea, M.K.; Pfeiler, G.; Fink-Retter, A.; Hansen, T.V.O.; Ejlertsen, B.; Johannsson, O.T.; Offit, K.; Kirchhoff, T.; Gaudet, M.M.; Vijai, J.; Robson, M.; Piedmonte, M.; Phillips, K.A.; L. van le; Hoffman, J.S.; Toland, A.E.; Montagna, M.; Tognazzo, S.; Imyanitov, E.; Isaacs, C.; Janavicius, R.; Lazaro, C.; Blanco, I.; Tornero, E.; Navarro, M.; Moysich, K.B.; Karlan, B.Y.; Gross, J.; Olah, E.; Vaszko, T.; Teo, S.H.; Ganz, P.A.; Beattie, M.S.; Dorfling, C.M.; Rensburg, E.J. van; Diez, O.; Kwong, A.; Schmutzler, R.K.; 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.; Schaefer, D.; Caldes, T.; Hoya, M. de la; Nevanlinna, H.; Aittomaki, K.; Plante, M.; Spurdle, A.B.; Neuhausen, S.L.; Ding, Y.C.; Wang, X.S.; Lindor, N.; Fredericksen, Z.; Pankratz, V.S.; Peterlongo, P.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Bonanni, B.; Bernard, L.; Dolcetti, R.; Papi, L.; Ottini, L.; Radice, P.; Greene, M.H.; Mai, P.L.; Andrulis, I.L.; Glendon, G.; Ozcelik, H.; Pharoah, P.D.P.; Gayther, S.A.; Simard, J.; Easton, D.F.; Couch, F.J.; Chenevix-Trench, G.; SWE-BRCA; HEBON; EMBRACE; GEMO; KConFab; Ocgn; Consortium Investigators Modifiers
• Date: 2012-04-28
• Journal: Human Mutation
• Volume: 33
• Issue: 4
• Pages: 690 - 702
• DOI: doi:10.1002/humu.22025