Analysis of MGMT promoter methylation status in high grade glioma patients with long term and conventional survival times: A retrospective study

Abstract

2084 Background: Response to alkylating chemotherapy in patients with high grade gliomas (HGG) has been found correlated to epigenetic silencing of the DNA repair gene MGMT (O6-methylguanine-DNA methyltransferase) in the tumor tissue. Patients with HGG expressing a methylated MGMT promoter benefited from alkylating chemotherapy in terms of a prolonged survival as compared to patients with unmethylated MGMT promoter. Methods: Our study cohort comprised 47 patients with HGG, all treated with concomitant chemotherapy and radiotherapy in our institution. 23/47 patients (8 women, 15 men, aged 22.4–64.5 years, median 36.3) survived longer than 36 months (range of survival times 36–137 months, in median 46.9 months) and were defined as long term survivors (LS). 24/47 patients (5 women and 19 men, aged 18.3–73.3 years, median 47.7) with early tumor relapse who survived in median for 23.5 months were defined as HGG patients with conventional survival (CS). In all cases, we extracted DNA from formalin-fixed and paraffin-embedded tumor tissue samples. The methylation status of the MGMT promoter was determined by bisulfide modification of the DNA and methylation-specific polymerase-chain- reaction (MSP). MSP results were rated by 4 independent observers. Results: There was high interobserver agreement at interpretation of MSP results (range of kappa values: 0.71–0.87). Among LS, we found MGMT promoter methylation in 13/24 (81.5%) patients and an unmethylated MGMT promoter in 3 patients, whereas the MSP results were not interpretable in 7 patients of this patient subgroup. Among CS, we found promoter methylation in 16 patients (66.6%), unmethylated promoter in 6 patients and uninterpretable results in one patient. There was no statistically significant difference in MGMT promoter methylation rate between LS and CS. Conclusions: The proportion of gliomas with methylated MGMT promoter in this series is unexpectedly high, particularly for CS patients. Potential explanations for this finding are methodological differences due to the use of paraffin-embedded tumors instead of frozen tumor material as in most published series and a potential random accumulation of MGMT positive tumors in the patients with CS survival. No significant financial relationships to disclose.