REVIEW MGMT promoter methylation in malignant gliomas Markus J. Riemenschneider & Monika E. Hegi & Guido Reifenberger Received: 24 July 2010 / Accepted: 4 August 2010 / Published online: 20 August 2010 # Springer-Verlag 2010 Abstract The O 6 -methylguanine-DNA methyltransferase (MGMT) gene is located at chromosome 10q26 and codes for a DNA repair enzyme that—if active—can counteract the effects of alkylating chemotherapy. Malignant gliomas often have the MGMT gene inactivated due to aberrant methylation of its promoter region. The assessment of the MGMT promoter methylation status has become of clinical relevance as a molecular marker associated with response to alkylating chemotherapy and prolonged survival of glio- blastoma patients. MGMT promoter methylation testing is also on the merge of being used as a marker for patient selection within clinical trials, e.g., the current CENTRIC trial that is specifically focusing on patients with MGMT promoter-methylated glioblastomas. In anaplastic gliomas, MGMT promoter methylation is a favorable prognostic marker independent of the type of therapy, i.e., radio- or chemotherapy. This occurrence might be associated with the high incidence of other prognostically favorable molecular markers in these tumors, such as IDH1 mutation, 1p/19q deletion or yet to be identified novel aberrations. A variety of different methods are being used to assess MGMT promoter methylation in clinical samples, which may give rise to inter-laboratory variations in test results. Immunohistochemical determination of MGMT protein expression has not proven reliable for diagnostic purposes. This brief review article aims to summarize the main aspects of MGMT promoter methylation testing in contem- porary neuro-oncology, in particular its value as a clinically useful molecular marker, putting it into the context of other molecular markers of clinical use in gliomas of adult patients. Keywords Glioma . O 6 -methylguanine-DNA methyltransferase (MGMT) . Molecular diagnostics . Prognosis . Promoter methylation The MGMT gene encodes a DNA repair protein that removes alkyl groups from the O 6 position of guanine, an important site of DNA alkylation [1]. Chemotherapy-induced alkyl- ation at this site triggers cytotoxicity and apoptosis. Tumor cells that express high levels of the MGMT repair protein may thereby counteract the therapeutic effect of alkylating agents, including nitrosourea compounds and temozolomide that are most commonly used for the treatment of malignant gliomas. MGMT is epigenetically inactivated via hyper- methylation of the 5′-CpG island in approximately 40% of primary glioblastomas and over 70% of secondary glioblas- tomas (Fig. 1)[2]. MGMT promoter methylation is also found in half of the diffuse and anaplastic astrocytomas as well as approximately two thirds of the oligodendroglial and mixed tumors [2]. CpG islands are defined as genomic regions that contain a higher than average frequency of CG dinucleotides (CpG sites) and are involved in regulation of gene transcription. CpG islands, including the one associated with the MGMT gene, often span the transcription start site of genes and contain crucial transcription factor binding sites. Aberrant methylation of CpG islands may impair gene transcription, which consequently leads to reduced or even complete loss of expression of the respective gene product M. J. Riemenschneider : G. Reifenberger (*) Department of Neuropathology, Heinrich-Heine-University, Moorenstr. 5, 40225 Duesseldorf, Germany e-mail: reifenberger@med.uni-duesseldorf.de M. E. Hegi Department of Neurosurgery, Laboratory of Brain Tumor Biology and Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Targ Oncol (2010) 5:161–165 DOI 10.1007/s11523-010-0153-6