Abstract 1998: Aberrant methylation of BRCA/HR pathway genes and response to platinum-taxane therapy in ovarian cancer

Women diagnosed with ovarian cancer generally receive debulking surgery in combination with platinum-taxane based chemotherapy. While this treatment is currently the most effective, women diagnosed with Stage III and IV ovarian cancer have a less than a 20% five-year survival rate. Ovarian tumorigenesis is a multi-step process that results from the sequential accumulation, and interplay, of genetic and epigenetic mutations in critical genes. It is likely that such mutations underlie the different responses to therapy. There are several reports that demonstrate that women with germline mutations in BRCA genes and inherited ovarian cancer have a favorable survival as compared to women with sporadic ovarian cancer that is matched for pathological stage. The BRCA1 and BRCA2 genes function to repair DNA damage and maintain genetic stability through the homologous recombination (HR) repair pathway. Much of the superior survival is likely due to hypersensitivity to platinum-containing chemotherapy that in turn is due to incompetent DNA repair of platinum DNA adducts due to faulty HR repair of double stranded DNA breaks (DSBs). It is hypothesized that sporadic ovarian tumors, which constitute the vast majority of ovarian cancer, with epigenetic suppression of BRCA or BRCA-associated proteins, e.g. aberrant promoter hypermethylation of BRCA1, will be relatively hypersensitive to platinum as compared to ovarian tumors with an intact BRCA/HR pathway. To answer this important question, we have used bisulfite sequencing and quantitative methylation specific PCR to examine the incidence of epigenetic impairment of BRCA/HR pathway genes, including BRCA1, PALB2 and other genes, in primary human epithelial ovarian cancer and, using these results, then examined the relative frequency of BRCA/HR pathway impairment in sporadic ovarian tumors separated into cohorts by time to progression after platinum-taxane therapy and other measures of outcome. 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 1998. doi:10.1158/1538-7445.AM2011-1998