MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma

Abstract

Hypermethylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) gene has been shown to be associated with improved outcome in glioblastoma (GBM) and may be a predictive marker of sensitivity to alkylating agents. However, the predictive utility of this marker has not been rigorously tested with regard to sensitivity to other therapies, namely radiation. To address this issue, we assessed MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy as a component of adjuvant treatment. Formalin-fixed, paraffin-embedded tumor samples from 225 patients with newly diagnosed GBM were analyzed via methylation-specific, quantitative real-time polymerase chain reaction following bisulfite treatment on isolated DNA to assess MGMT promoter methylation status. In patients who received radiotherapy alone following resection, methylation of the MGMT promoter correlated with an improved response to radiotherapy. Unmethylated tumors were twice as likely to progress during radiation treatment. The median time interval between resection and tumor progression of unmethylated tumors was also nearly half that of methylated tumors. Promoter methylation was also found to confer improved overall survival in patients who did not receive adjuvant alkylating chemotherapy. Multivariable analysis demonstrated that methylation status was independent of age, Karnofsky performance score, and extent of resection as a predictor of time to progression and overall survival. Our data suggest that MGMT promoter methylation appears to be a predictive biomarker of radiation response. Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM.

Fig. 1.

MGMT qRT-PCR curves. qRT-PCR shows amplification of methylated MGMT promoter (green curve), unmethylated MGMT promoter (blue curve), and a COL2A1 control (red curve). (A) Example of a tumor with MGMT promoter methylation; (B) Example of a tumor without MGMT promoter methylation.

Fig. 2.

Progression-free survival and MGMT promoter methylation status. Kaplan–Meier curves showing progression-free survival for patients with methylated (dotted line) vs unmethylated (solid line) tumors.

Fig. 3.

Overall survival and MGMT promoter methylation status. Kaplan–Meier curves showing overall survival for patients with methylated (dotted line) vs unmethylated (solid line) tumors.