Inactivation of the DNA-Repair Gene<i>MGMT</i>and the Clinical Response of Gliomas to Alkylating Agents

TLDR

MGMT repairs O6‑methylguanine lesions, and its promoter methylation silences the gene, thereby reducing tumor resistance to alkylating agents. The study aimed to assess whether MGMT promoter methylation predicts glioma responsiveness to alkylating chemotherapy. MGMT promoter methylation status was determined in tumor DNA using a methylation‑specific PCR assay on gliomas from patients treated with carmustine. MGMT promoter methylation occurred in 40 % of tumors and was independently associated with tumor regression, longer overall and disease‑free survival, making it a strong predictor of response to alkylating agents.

Abstract

The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents.We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome.The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status.Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.