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

Abstract

The DNA repair enzyme O6-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 (O6-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

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Figure 1: Map of the CpG island region of the MGMT promoter.
Figure 2: Methylation of the CpG island region of the MGMT promoter.
Figure 3: Immunochemical staining for MGMT protein expression in glioblastomas.
Figure 4: Bisulfite conversion of tumor DNA.
Figure 5: Frequency of MGMT promoter methylation in glioma subtypes.

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Correspondence to Michael Weller.

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M. Weller has acted as a consultant for Merck Serono, OncoMethylome Sciences and Schering-Plough, has received honoraria from Merck Serono and Schering-Plough, and has received research support from Merck Serono. R. Stupp has acted as a consultant for and received honoraria from Merck Serono and Schering-Plough, and has acted as a consultant for Oncomethylome Sciences. G. Reifenberger has received honoraria from Essex Pharma, and has acted as a consultant for Miltenyi Biotec and OncoMethylome Sciences. A. A. Brandes has acted as a consultant for OncoMethylome Sciences and Schering-Plough, and has received honoraria from Schering-Plough. M. J. van den Bent has acted as a consultant for Merck AG, OncoMethylome Sciences and Schering-Plough, has received honoraria from Schering-Plough, and has received research support from OncoMethylome Sciences and Schering-Plough. W. Wick has acted as a consultant for and received honoraria from Merck Serono and Schering-Plough. M. Hegi has acted as a consultant for and received research support from OncoMethylome Sciences and Merck Serono, and has received honoraria from OncoMethylome Sciences and Schering-Plough.

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Weller, M., Stupp, R., Reifenberger, G. et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine?. Nat Rev Neurol 6, 39–51 (2010). https://doi.org/10.1038/nrneurol.2009.197

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