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.
We analyzed copy number alteration (CNV) and methylation profiles of 1095 primary and 92 progressive Isocitrate dehydrogenase (IDH) 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.
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 three methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including GBX2 were found to be hypermethylated and downregulated on mRNA level in mMGMT tumors. In progressive glioblastomas, PDGFRA and GLI2 amplifications were enriched in mMGMT tumors. mMGMT tumors gain PDGFRA amplification whereas uMGMT tumors with PDGFRA amplifications frequently lose this amplification upon progression. Glioblastoma patients surviving < 6 months and mMGMT harbored less frequent EGFR amplifications, more frequent TP53 mutations and a higher TNF-NFκB pathway activation compared to patients surviving longer than 12 months.
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.
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