BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases

Abstract

Background: It is estimated that more than 20% of ovarian cancer cases are associated with a genetic predisposition that is only partially explained by germline mutations in the BRCA1 and BRCA2 genes. Recently, several pieces of evidence showed that mutations in three genes involved in the homologous recombination DNA repair pathway, i.e., BRIP1, RAD51C, and RAD51D, are associated with a high risk of ovarian cancer. To more precisely estimate the ovarian cancer risk attributed to BRIP1, RAD51C, and RAD51D mutations, we performed a meta-analysis based on a comparison of a total of~29,400 ovarian cancer patients from 63 studies and a total of~116,000 controls from the gnomAD database. Results: The analysis allowed precise estimation of ovarian cancer risks attributed to mutations in BRIP1, RAD51C, and RAD51D, confirming that all three genes are ovarian cancer high-risk genes (odds ratio (OR) = 4.94, 95%CIs:4.07-6.00, p < 0.0001; OR = 5.59, 95%CIs:4.42-7.07, p < 0.0001; and OR = 6.94, 95%CIs:5.10-9.44, p < 0.0001, respectively). In the present report, we show, for the first time, a mutation-specific risk analysis associated with distinct, recurrent, mutations in the genes. Conclusions: The meta-analysis provides evidence supporting the pathogenicity of BRIP1, RAD51C, and RAD51D mutations in relation to ovarian cancer. The level of ovarian cancer risk conferred by these mutations is relatively high, indicating that after BRCA1 and BRCA2, the BRIP1, RAD51C, and RAD51D genes are the most important ovarian cancer risk genes, cumulatively contributing to~2% of ovarian cancer cases. The inclusion of the genes into routine diagnostic tests may influence both the prevention and the potential treatment of ovarian cancer.

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

“…Ramus et al described a relative risk associated with protein truncating variants in BRIP1 of 11.2 (95% CI 3.2–34.1), with an estimated cumulative risk of 5.8% (95% CI 3.6–9.1%) by the age of 80 years [ 11 ] ( Table 2 ). The association between protein truncating variants in BRIP1 and risk of ovarian cancer has been confirmed in other analyses (associated risks ranged from 2.6 to 6.4 [ 27 , 28 , 29 , 35 , 45 ]) ( Table 2 and Table 3 ). The frequency of protein truncating variants in population-based studies, separated by ovarian cancer histotypes are given in Table 2 , and the frequency in the other retrospective studies, mostly family studies or with women referred to clinical testing, are given in Table 3 .…”

“… Abbreviations: RR —Relative risk; OR—odds ratio; SRR—Standardized risk ratio; PVs—Pathogenic variants; -: Not available, NC: Not calculated, a ExAC NFE non-TCGA, b gnomAD NFE non-TCGA, ¶ deleterious missense changes included, ^ [ 45 ] Overlapped with 6 studies included in this review; ^^ [ 29 ] Overlapped with 1 study included in this review; # Segregation analysis. Bold: highlight info.…”

Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene

“…Yet, we think that is worth considering this possibility for variants expressing the variable proportion of (likely) functional mRNAs (see Supplementary Methods) 11 [46]. 12 [47].…”

Recurrent Mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish Patients with Ovarian Cancer

“…The most important genetic causes of ovarian cancer are mutations in BRCA1 and BRCA2 genes, which account for up to 15% of all cases [ 11 , 12 , 13 , 14 ]. BRCA1 and BRCA2 encode proteins involved in recombinational repair of damaged DNA [ 11 ] and it has been found that mutations in other genes involved in the repair of DNA damage by homologous recombination, including e.g., RAD51C , RAD51D , BRIP1 , PALB2 , and CHEK2 may be associated with ovarian cancer risk [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”