Journal Article

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Brandes, Alba A., Wick, Wolfgang, Hegi, Monika E., Weller, Michael, Reifenberger, Guido, van den Bent, Martin J., Stupp, Roger

2010

Overview

The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the effects of alkylating agents, and its expression is associated with resistance to cancer therapy based on these compounds. Weller et al . consider the prognostic and predictive value of MGMT gene silencing in gliomas and describe the assays that are commonly used to evaluate MGMT status, focusing particularly on MGMT promoter methylation, which is the key mechanism of MGMT gene silencing. The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice. Key Points MGMT ( O 6 -methylguanine-DNA methyltransferase) promoter methylation has become the most powerful molecular prognosticator in malignant gliomas MGMT promoter methylation is predictive for response to alkylating agent chemotherapy in glioblastoma Methylation-specific PCR is the only validated technique to derive prognostic information from determination of the MGMT status The MGMT status has become a parameter for stratification of patients with glioma within clinical trials

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Antineoplastic Agents, Alkylating - pharmacology / Antineoplastic Agents, Alkylating - therapeutic use / Care and treatment / Chemotherapy / Clinical trials / Development and progression / DNA methylation / DNA Methylation - genetics / DNA Modification Methylases - genetics / DNA repair / DNA Repair Enzymes - genetics / Enzymes / Gene expression / Gene Silencing - drug effects / Genetic aspects / Glioma - drug therapy / Glioma - genetics / Gliomas / Health aspects / Humans / Medicine / Medicine & Public Health / Methylation / Methyltransferases / Neurology / Oncology / Physiological aspects / Precision medicine / Precision Medicine - methods / Precision Medicine - trends / Promoter Regions, Genetic - drug effects / Promoter Regions, Genetic - genetics / Promoters (Genetics) / Proteins / Reproducibility / review-article / Risk factors / Standardized tests / Tumor Suppressor Proteins - genetics / Tumors