Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Abstract

Background: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.

Methods: We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.

Results: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.

Conclusion: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

Figure 1

Forest plots of study-specific associations between the single-nucleotide polymorphism (SNP) rs3814113 and ovarian cancer risk among BRCA1 or BRCA2 mutation carriers. Study-specific per-allele hazard ratio estimates are presented. A) BRCA1 mutation carriers. B) BRCA2 mutation carriers. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines = 95% confidence intervals; diamonds = the summary for all of Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Some of the smaller studies of BRCA2 mutation carriers have been combined with other studies from the same country. Study names are as follows: BCFR = Breast Cancer Family Registry; BFBOCC = Baltic Familial Breast and Ovarian Cancer Consortium; CBCS = Copenhagen Breast Cancer Study; CNIO = Spanish National Cancer Centre; CONSIT TEAM = CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella; DKFZ = Deutsches Krebsforschungszentrum; DNA HEBON = HEreditary Breast and Ovarian study Netherlands; EMBRACE = Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers; FCCC = Fox Chase Cancer Center; GC-HBCO = German Consortium of Hereditary Breast and Ovarian Cancer; GEMO = Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers; HCSC = Hospital Clinico San Carlos; HEBCS = Helsinki Breast Cancer Study; ICO = Institut Català d’Oncologia; IHCC = International Hereditary Cancer Centre; ILUH = Iceland Landspitali—University Hospital; INHERIT = Interdisciplinary Health Research International Team Breast Cancer Susceptibility; IOVHBOCS = Istituto Oncologico Veneto Hereditary Breast and Ovarian Cancer Study; KCONFAB = Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer; MAYO = Mayo Clinic; MSKCC = Memorial Sloane Kettering Cancer Center; NCI = National Cancer Institute; NNPIO = N. N. Petrov Institute of Oncology; OCGN = Ontario Cancer Genetics Network; OUH = Odense University Hospital; PBCS = Pisa Breast Cancer Study; SWE-BRCA = Swedish Breast Cancer Study; UCI = University of California Irvine; UCSF = University of California San Francisco; UKGRFOCR = UK and Gilda Radner Familial Ovarian Cancer Registries; UPENN = University of Pennsylvania; WCRI = Women’s Cancer Research Institute.