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Neuro Oncol. 2018 Feb 19;20(3):367-379. doi: 10.1093/neuonc/nox160.

Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation.

Author information

1
Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Department of Neurology, Heidelberg University Hospital, Germany.
3
Clinical Cooperation Unit Neuropathology, DKTK, DKFZ, Heidelberg, Germany.
4
Department of Neuropathology, Heidelberg University Hospital, Germany.
5
Brain Tumor Metabolism, DKFZ, Heidelberg, Germany.
6
Department of Neuropathology, Heinrich Heine University Hospital, Düsseldorf, Germany.
7
Department of Neurosurgery, Heinrich Heine University Hospital, Düsseldorf, Germany.
8
Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology & Neurosurgery, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University Tübingen, DKTK, DKFZ partner site Tübingen.
9
Center for Personalized Medicine, Eberhard Karls University Tübingen.
10
Center for CNS Tumors at Comprehensive Cancer Center Tübingen-Stuttgart, Tübingen, Germany.
11
Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
12
Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany.
13
Department of Neurosurgery, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
14
Department of Radiation Oncology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany, DKTK partner site Freiburg; and DKFZ Heidelberg, Germany.
15
Genomics and Proteomics Core Facility, Microarray Unit, DKFZ, Heidelberg, Germany.
16
Division of Pediatric Neurooncology, DKTK, DKFZ, Heidelberg, Germany.
17
Department of Pediatric Oncology, Haematology and Immunology, Heidelberg University Hospital, and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
18
Department of Neurology, University Hospital Zürich, Zürich, Switzerland.
19
Department of Neuroradiology, Heidelberg University Hospital, Germany.
20
Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKTK, DKFZ, Heidelberg, Germany.
21
Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Abstract

Background:

O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma. We investigated whether this marker furthermore defines a molecularly distinct tumor subtype with clinically different outcome.

Methods:

We analyzed copy number variation (CNV) and methylation profiles of 1095 primary and 92 progressive isocitrate dehydrogenase wildtype glioblastomas, including paired samples from 49 patients. DNA mutation data from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA and 55 Chinese Glioma Genome Atlas samples were analyzed.

Results:

Among untreated glioblastomas, MGMT promoter methylated (mMGMT) and unmethylated (uMGMT) tumors did not show different CNV or specific gene mutations, but a higher mutation count in mMGMT tumors. We identified 3 methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including gastrulation brain homeobox 2 (GBX2) were found to be hypermethylated and downregulated on the mRNA level in mMGMT tumors. In progressive glioblastomas, platelet derived growth factor receptor alpha (PDGFRA) and GLI2 amplifications were enriched in mMGMT tumors. Methylated MGMT tumors gain PDGFRA amplification of PDGFRA, whereas uMGMT tumors with amplified PDGFRA frequently lose this amplification upon progression. Glioblastoma patients surviving <6 months and with mMGMT harbored less frequent epidermal growth factor receptor (EGFR) amplifications, more frequent TP53 mutations, and a higher tumor necrosis factor-nuclear factor-kappaB (TNF-NFκB) pathway activation compared with patients surviving >12 months.

Conclusions:

MGMT promoter methylation status does not define a molecularly distinct glioblastoma subpopulation among untreated tumors. Progressive mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have more unfavorable molecular profiles.

PMID:
29016808
PMCID:
PMC5817966
DOI:
10.1093/neuonc/nox160
[Indexed for MEDLINE]
Free PMC Article

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