Key Points
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O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts responsiveness to alkylating chemotherapies in glioblastoma, but is not a prognostic biomarker in gliomas lacking isocitrate dehydrogenase gene mutations
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Treatment decisions in elderly patients with glioblastoma should take MGMT promoter methylation status into account
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MGMT testing to select patients with glioblastoma for clinical trials is feasible, and withholding temozolomide from patients without MGMT promoter methylation is justified in this context
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MGMT-mediated resistance to alkylating chemotherapy is not overcome by alternative dosing schedules, but might be circumvented by the use of alternative treatments
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Epigenetic inactivation of MGMT might facilitate the induction of point mutations in TP53 and other oncogenes during tumorigenesis and tumour progression
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Quality-assured MGMT testing should be implemented as a molecular diagnostic method in the next WHO classification of brain tumours
Abstract
Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65–70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed.
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Acknowledgements
The authors thank David Capper and Benedikt Wiestler for useful discussions and the provision of data obtained from searches of The Cancer Genome Atlas database.
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W.W., M.v.d.B., M. Weiler, C.P., M.H., M.P and G.R. researched data for the article. W.W., M. Weller, M.S., M. Weiler, A.v.D., C.P., M.H. and G.R. made substantial contributions to the discussion of content. W.W., M. Weller, M.v.d.B., M.H., M.P. and G.R. contributed equally to writing the article. All authors contributed to the review and editing of the manuscript before submission.
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W.W. has received consulting and lecture fees from MagForce, Merck Sharp & Dohme, and Roche, and research support from Apogenix, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Roche. He also serves on the Steering Committees of the AVAglio and CENTRIC trials, and is lead investigator of other trials in glioma. M. Weller has received research grants from Isarna Therapeutics, Bayer, Merck Serono, Merck Sharp & Dohme and Roche, and honoraria for lectures or advisory boards from Isarna Therapeutics, MagForce, Merck Serono, Merck Sharp & Dohme and Roche. M.v.d.B. acts as a consultant and is a member of the speakers' bureau for Merck Sharp & Dohme. M.S. has received honoraria from Merck Serono. M.H. has acted as a consultant for MDx Health, Merck Serono, Merck Sharp & Dohme and Roche. M.P. has received consultancy and lecture fees from Medac, Merck Serono, and Novartis, and research support from Merck Serono and Novartis. G.R. has received a research grant from Roche, and honoraria from Merck Serono and Roche. The other authors declare no competing interests.
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Wick, W., Weller, M., van den Bent, M. et al. MGMT testing—the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10, 372–385 (2014). https://doi.org/10.1038/nrneurol.2014.100
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DOI: https://doi.org/10.1038/nrneurol.2014.100
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