The Prevalence And Clinical Significance Of Mutations BRIP 1 , BARD 1 , PALB 2 And NBN Genes In Women With Ovarian Cancer

Several genes functioning in DNA repair pathways confer susceptibility to epithelial ovarian cancer (EOC). We evaluated the prevalence of coding sequence mutations in 4 DNA repair genes BRIP1, BARD1, NBN1, and PALB2 in 3,236 invasive EOC cases and 3,431 controls of European ancestry, and in 2,133 BRCA1/BRCA2 negative, unaffected women from the UK Familial Ovarian Cancer Screening Study (UKFOCSS), a clinical screening trial for ovarian cancer. We found significant evidence of an increased frequency of deleterious mutations in BRIP1 in cases (0.9 percent) compared to controls (0.09 percent) (P=0.0001), but no differences in case/control mutation frequency for BARD1 (P=0.39), NBN1 (P=0.61), or PALB2 (P=0.078). We identified a non-random distribution of mutations in the BRIP1 gene (P=0.0085) indicating there is a correlation between mutation location and occurrence of ovarian cancer. BRIP1 mutation carriers tended to be diagnosed at a later age (P=0.072), with highgrade serous disease (P=0.049), and at a later stage (P=0.093) compared to non-carriers. Using data from non-family based case-control studies we estimated the relative risks associated with BRIP1 mutations to be 11 for invasive EOC (95% confidence interval (CI) 3.2 – 34; P = 1 x 10-4) and 14 for high-grade serous ovarian cancer (95% CI 4.0 – 45; P = 2 x 10-5). We also performed segregation analysis using family data from case-control studies and from UKFOCSS, estimating the average relative risks in BRIP1 mutation carriers to be 3.4 (95% CI: 2.1 5.5, p=7×10-7) compared to the UK general population. These data have implications for genetic risk prediction and clinical intervention strategies for the prevention of ovarian cancer.