BRCA1 and MGMT gene promoter methylation predicts for chemoresponsiveness in epithelial ovarian cancer [EOC]

1047 BACKGROUND: Ovarian cancer is the second most common and most fatal of the gynaecological malignancies. Platinum-based combination chemotherapy is the mainstay of treatment of ovarian cancer. These agents act by inducing DNA damage and apoptosis and so genes regulating these processes such as BRCA1, MGMT, MLH1, RASSF1A may be involved in determining tumor chemoresponsiveness. CpG island methylation of gene promoters is frequently altered in cancer and has been implicated in response to chemotherapy. OBJECTIVE: To determine the methylation status of BRCA1, MGMT, MLH1, RASSF1A and p16 genes and to correlate the methylator phenotypes to chemoresponsiveness as determined clinically. METHODS: Thirty-five women with FIGO stage III epithelial ovarian cancer underwent surgical cytoreduction followed by platinum-based chemotherapy regimen. After an informed consent, a portion of the tumor was snap frozen for molecular analysis.The methylation-specific polymerase chain reaction (MS-PCR) technique was employed to assay the methylation status of the gene promoters. The response to platinum-based chemotherapy was documented clinically, radiologically and by serial CA-125 levels. At the end of 6 cycles of chemotherapy, based on their initial response, two groups were identified: Primary chemosensitive (PCs, n=24) and primary chemoresistant (PCr, n=11). The patients were further followed up [9-33 mo], on the basis of which, two groups were identified: No Evidence of Disease (NED, n=15) and Evidence of disease [ED (Stable/Progressive Disease), n=20]. Statistical analysis was performed on these groups by the Pearson’s Chi-square test. RESULTS: Frequent methylation was observed for BRCA1 (48%) and RASSF1A (37%) genes. Methylation frequency of p16, MGMT and MLH1 were 25%, 20% and 5% respectively. Methylated BRCA1 (p MGMT (p=0.05) showed a significant correlation to primary chemosensitivity. Further, methylated BRCA1 (p=0.05) and p16 (p=0.03) predicted for No Evidence of Disease at a mean follow-up period of 18months [Range 9-33 mo].Methylation of at least one of the group of genes involved in DNA repair/cell cycle (BRCA1, MGMT and p16) was associated with improved response to chemotherapy (p = 0.002). CONCLUSION: In EOC, methylation profiling of a limited number of genes involved in DNA repair such as BRCA1 and MGMT is useful in prediction of response to chemotherapy. This is particularly applicable in a low-resource setting where high-throughput approaches are not available. BRCA1 and p16 gene methylation status are also promising prognostic markers.