Abstract
BackgroundIt 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.ResultsThe 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.ConclusionsThe 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.
Highlights
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
Mutations in BRCA1/2 genes result in homologous recombination (HR) deficiency which may be utilized in the treatment of Ovarian cancer (OC) with platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors [6, 8,9,10]
To precisely estimate the OC risk associated with mutations in BRIP1, RAD51 homolog C (RAD51C), and RAD51 paralog D (RAD51D), we searched for studies that provided information on mutation frequency in the abovementioned genes in OC cases and compared these data to the mutation frequencies in population controls from the publicly available Genome Aggregation Database (gnomAD) database
Summary
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. 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. A strategy applying preventive genetic testing seems to be very attractive, especially for OC, as more than 20% of women diagnosed with OC have a hereditary tendency to develop the disease, harboring a lossof-function mutation in one of the already known cancer-related genes [3, 4]. Even up to 50% of OC exhibit HR deficiency (most commonly high-grade serous OC), a substantial fraction of OC patients may benefit from therapeutic approaches based on PARP inhibitors [16]
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