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Nat Rev Neurol. 2014 Jul;10(7):372-85. doi: 10.1038/nrneurol.2014.100. Epub 2014 Jun 10.

MGMT testing--the challenges for biomarker-based glioma treatment.

Author information

1
German Cancer Consortium, Clinical Cooperation Units Neuro-oncology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
2
Department of Neurology, University Hospital Zurich, Switzerland.
3
Department of Neurology/Neuro-oncology, Erasmus MC Cancer Institute, Netherlands.
4
Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, France.
5
Neuropathology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
6
Division of Epigenetics and Risk Factors, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
7
Department of Clinical Neurosciences, University Hospital Lausanne, Switzerland.
8
Neuroimmunology and Brain Tumour Immunology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
9
Department of Neuropathology, Heinrich Heine University, Germany.

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 O(6)-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.

PMID:
24912512
DOI:
10.1038/nrneurol.2014.100
[Indexed for MEDLINE]
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