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Review
. 2019 Feb 14;21(2):167-178.
doi: 10.1093/neuonc/noy132.

MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges

Alireza Mansouri  1 , Laureen D Hachem  1 , Sheila Mansouri  2 , Farshad Nassiri  1   2 , Normand J Laperriere  3 , Daniel Xia  4 , Neal I Lindeman  5 , Patrick Y Wen  6 , Arnab Chakravarti  7 , Minesh P Mehta  8 , Monika E Hegi  9 , Roger Stupp  10 , Kenneth D Aldape  11 , Gelareh Zadeh  1   2   12
Affiliations
Review

MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges

Alireza Mansouri et al. Neuro Oncol. .

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a universally poor prognosis. The emergence of molecular biomarkers has had a significant impact on histological typing and diagnosis, as well as predicting patient survival and response to treatment. The methylation status of the O6-methylguanine-DNA methyl-transferase (MGMT) gene promoter is one such molecular biomarker. Despite the strong evidence supporting the role of MGMT methylation status in prognostication, its routine implementation in clinical practice has been challenging. The methods and optimal cutoff definitions for MGMT status determination remain controversial. Variation in detection methods between laboratories presents a major challenge for consensus. Moreover, consideration of other clinical and genetic/epigenetic factors must also be incorporated into treatment decision making. In this review, we distill the available evidence to summarize our position on the optimal use of available assays, and propose strategies for resolving cases with equivocal methylation status and a framework for incorporating this important assay into research and clinical practice.

Keywords: MGMT; diagnostic; glioma; methylation; molecular markers; prognostic.

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Figures

Fig. 1
Fig. 1
MGMT promoter region and commonly used methylation assays. The promoter region and exon 1 of the MGMT gene contain the CpG island which spans 97 CpG sites. Methylation of CpG sites within 2 regions, DMR1 and DMR2, has been shown to negatively influence transcription. Five commonly methylated CpG sites within DMR2 are shown. The assays require isolation of DNA, followed by quality check (QC) for purity and integrity of the DNA. The efficiency of bisulfite conversion should also be tested to avoid false negative results. PSQ: pyrosequencing; TF: transcription factor; TSS: transcription start site.
Fig. 2
Fig. 2
Proposed management algorithm for patients with glioblastomas, based on methylation status and other clinical parameters. PSQ: pyrosequencing; KPS: Karnofsky performance status; ECOG: Eastern Cooperative Oncology Group.
See this image and copyright information in PMC

References

    1. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol. 2002;4(4):278–299. - PMC - PubMed
    1. Hegi ME, Diserens AC, Gorlia T, et al. . MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003. - PubMed
    1. Stupp R, Hegi ME, Mason WP, et al. ; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. - PubMed
    1. Stupp R, Mason WP, van den Bent MJ, et al. ; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. - PubMed
    1. Bady P, Delorenzi M, Hegi ME. Sensitivity analysis of the MGMT-STP27 model and impact of genetic and epigenetic context to predict the MGMT methylation status in gliomas and other tumors. J Mol Diagn. 2016;18(3):350–361. - PubMed