Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10] Timothy R. Rebbeck1,2, Nandita Mitra2, Susan M. Domchek1,3, Fei Wan2, Shannon Chuai2, Tara M. Friebel2, Saarene Panossian2, Amanda Spurdle5, Georgia Chenevix-Trench5, kConFab6, Christian F. Singer7, Georg Pfeiler7, Susan L. Neuhausen8, Henry T. Lynch9, Judy E. Garber10, Jeffrey N. Weitzel12, Claudine Isaacs13, Fergus Couch14, Steven A. Narod15, Wendy S. Rubinstein16, Gail E. Tomlinson17,19, Patricia A. Ganz20, Olufunmilayo I. Olopade21, Nadine Tung11, Joanne L. Blum18, Roger Greenberg1,3, Katherine L. Nathanson1,3 and Mary B. Daly