Abstract 908A: RAD51C germline mutations in breast and ovarian cancer cases from high-risk families

Abstract

Abstract Purpose: BRCA1 and BRCA2 account for approximately 80% of cases of hereditary breast and ovarian cancer. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene RAD51C, essential for homologous recombination repair, has been reported to be a rare breast cancer susceptibility gene. Several pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families but not in families with breast cancer alone. Methods: We performed complete sequencing of RAD51C in germline DNA of 286 female breast and ovarian cancer cases with a family history of breast and ovarian cancer. They had been previously tested for mutations in BRCA1 and BRCA2 and were negative. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancer. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of non-synonomous variants. Two-hybrid screening is currently being performed to assess functionality of four of the non-synonomous variants. Results: Fifteen DNA sequence variants were identified among the 286 cases; including four intronic, one 5’ UTR, one promoter, three synonymous, six non-synonymous variants. None were truncating. Of these variants, six have been previously identified and have rs numbers, whereas the remaining nine are novel. Nine of the variants were private (seen in one individual) and the other six were detected in more than one individual. Of the six non-synonomous variants, SIFT and Polyphen predicted that two were likely pathogenic, with predictions based on degree of conservation of the affected residue. An additional two non-synonomous variants are in important domains of the protein and may also be pathogenic. We are currently investigating potential functional importance of these four variants through yeast-two-hybrid assays. Conclusions: Our results provide further evidence that Rad51C is a breast and ovarian cancer susceptibility locus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 908A. doi:10.1158/1538-7445.AM2011-908A