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.