Differential MGMT Promoter Methylation Profiling between Low Grade and High Grade Papillary Serous Ovarian Carcinoma
F Abu Shahin, X Ji, P Hui, F Abudul-Karim, W Liu, B Yang. Cleveland Clinic, Cleveland, OH; Yale University, CT; Case Western Reserve University, Cleveland, OH
Background: Expression of O6-methylguanine-DNA methyl transferase (MGMT), a DNA repair protein, is regulated mainly by promoter methylation. Silencing of the MGMT gene through promoter methylation in brain cancer is associated with increased sensitivity to alkylating agents. It has also been shown that different genetic pathways exist between low grade papillary serous carcinoma (LG-PSC) and high grade papillary serous carcinoma (HG-PSC). However, differential epigenetic alteration, such as DNA methylation, between LG-PSC and HG-PSC has not been well characterized. We have compared the methylation status of MGMT between LG-PSC and HG-PSC and correlated MGMT methylation with clinicopathologic features.
Design: Sixty-three patients with ovarian PSC, including 40 cases of HG-PSC and 23 cases of LG-PSC, were included in this study. All cases, except one, were stage IIIc. The pathologic diagnosis was reviewed and clinicopathologic features were tabulated. Genomic DNA was extracted from paraffin embedded tissue. After bisulfite treatment, methylation of the MGMT gene was evaluated using pyrosequencing methylation assay.
Results: Methylation of MGMT was found in approximately 24% of 63 cases of ovarian PSC. The frequency of MGMT methylation was significantly different (P<0.001) between HG-PSC and LG-PSC. Methylation of MGMT promoter was seen in approximately 39% (15/40) of HG-PSC, but none of LG-PSC (0/23). In HG-PSC tumors, MGMT methylation status did not correlate with patients' age, bilaterality, residual disease after debulking, or sensitivity to chemotherapy.
Conclusions: Differential MGMT methylation profiling exists between LG-PSC and HG-PSC. No MGMT methylation was seen in LG-PSC compared to about 39% MGMT methylation in HG-PSC. Our study indicates that silencing of MGMT through methylation is involved in the carcinogenesis of HG-PSC. Our data further demonstrates that different epigenetic pathways exist between LG-PSC and HG-PSC.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 139, Wednesday Morning