LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild‐type glioblastoma patients

Andreas Mock, Christoph Geisenberger, Christian Orlik, Rolf Warta, Christian Schwager, Christine Jungk, Céline Dutruel, Lea Geiselhart, Dieter Weichenhan, Manuela Zucknick, Ann‐Katrin Nied, Sara Friauf, Janina Exner, David Capper, Christian Hartmann, Bernd Lahrmann, Niels Grabe, Jürgen Debus, Andreas von Deimling, Odilia Popanda, Christoph Plass, Andreas Unterberg, Amir Abdollahi, Peter Schmezer, Christel Herold‐Mende

MGMT promoter methylation status is currently the only established molecular prognosticator in IDH wild-type glioblastoma multiforme (GBM). Therefore, we aimed to discover novel therapy-associated epigenetic biomarkers. After enrichment for hypermethylated fractions using Methyl-CpG-Immunoprecipitation (MCIp), we performed global DNA methylation profiling for 14 long-term (LTS; >36 months) and 15 short-term (STS; 6-10 months) surviving GBM patients. Even after exclusion of the G-CIMP phenotype, we observed marked differences between the LTS and STS methylome. 1247 probes in 706 genes were hypermethylated in LTS and 463 probes in 305 genes were found to be hypermethylated in STS patients (p-value<0.05, log2 fold-change±0.5). We identified 13 differentially methylated regions (DMRs) with a minimum of 4 differentially methylated probes per gene. Indeed, we were able to validate a subset of these DMRs through a second, independent method (MassARRAY) in our LTS/STS training set (ADCY1, GPC3, LOC283731/ISLR2). These DMRs were further assessed for their prognostic capability in an independent validation cohort (n=62) of non-G-CIMP GBMs from the TCGA. Hypermethylation of multiple CpGs mapping to the promoter region of LOC283731 correlated with improved patient outcome (p=0.03). The prognostic performance of LOC283731 promoter hypermethylation was confirmed in a third independent study cohort (n=89), and was independent of gender, performance (KPS) and MGMT status (p=0.0485, HR=0.63). Intriguingly, the prediction was most pronounced in younger GBM patients (<60 years). In conclusion, we provide compelling evidence that promoter methylation status of this novel gene is a prognostic biomarker in IDH1 wild-type/non-G-CIMP GBMs. This article is protected by copyright. All rights reserved.