title: MGMT testing--the challenges for biomarker-based glioma treatment.
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.
authors.affiliation: German Cancer Consortium, Clinical Cooperation Units Neuro-oncology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Department of Neurology/Neuro-oncology, Erasmus MC Cancer Institute, Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: van den Bent
authors.affiliation: Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: German Cancer Consortium, Clinical Cooperation Units Neuro-oncology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Weiler
authors.affiliation: Neuropathology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Division of Epigenetics and Risk Factors, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Department of Clinical Neurosciences, University Hospital Lausanne, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Hegi
authors.affiliation: Neuroimmunology and Brain Tumour Immunology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000628:therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005910:Glioma / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D006801:Humans; D008958:Models, Molecular; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes