OS07.1 Molecular differences in IDH wild type glioblastoma according to MGMT promoter methylation status

Abstract

Background: O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a biomarker for patients with glioblastoma treated with alkylating agents. We investigated whether this marker just predicts the efficacy of alkylating chemotherapy or defines a molecularly distinct tumor subpopulation with clinically different outcome. Methods: Isocitrate dehydrogenase (IDH) 1/2 wild type MGMT promoter methylated (mMGMT) vs. unmethylated (uMGMT) glioblastomas were assessed for differences in copy number variation, methylation, mutation and RNA expression. We analyzed copy number variation and methylation profiles in a series of 1106 glioblastomas from the Heidelberg Neuropathology database, including 66 recurrent samples. DNA mutation data was obtained from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA). RNA expression data was obtained from 107 TCGA and 55 Chinese Glioma Genome Atlas samples. We investigated differences between short (< 6 months) and long survivors (> 12 months) in the TCGA dataset. Results: At primary diagnosis, mMGMT and uMGMT tumors did not show different copy number alterations or specific gene mutations, but a moderately higher mutation rate in mMGMT tumors. Most of the differentially methylated positions were hypermethylated in the mMGMT group. Gastrulation brain homeobox (GBX) 2, which promotes tumor growth in prostate cancer, was found to be hypermethylated and two-fold downregulated in the mMGMT group. TCGA expression subtypes showed a trend towards more proneural tumors in the mMGMT group and RNAseq data revealed increased expression of resistance-associated genes in uMGMT tumors. In the recurrent setting, platelet-derived growth factor receptor (PDGFR)A and GLI family zinc finger (GLI)2 amplifications were enriched in mMGMT tumors. Amplification of chromosome 19 and the C19MC oncogenic miRNA complex were more frequent in recurrent mMGMT tumors. These tumors also showed a hypermethylation of the protocadherin (PCDH) gene cluster at recurrence, which had been linked to aggressiveness in neuroblastoma. Glioblastoma patients with short survival and MGMT promoter methylation harbored less EGFR amplifications, more TP53 mutations and higher TNF-NFκB pathway activation compared to long survivors. Patients with uMGMT tumors and long survival showed an increased interferon signaling, which has been shown to downregulate MGMT and induce chemosensitivity. Conclusions:MGMT promoter methylation status serves as a biomarker for alkylating therapy and does not describe a molecular distinct glioblastoma subpopulation in the primary setting. However, recurrent mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have specific, more unfavorable molecular profiles, which could be a leverage point for further research.