BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5′ UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene.
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
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