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

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• 作者：Andreas Mock ; Christoph Geisenberger ; Christian Orlik ; Rolf Warta ; Christian Schwager ; Christine Jungk ; Cé ; line Dutruel ; Lea Geiselhart ; Dieter Weichenhan ; Manuela Zucknick ; Ann-Katrin Nied ; Sara Friauf ; Janina Exner ; David Capper ; Christian Hartmann ; Bernd Lahrmann ; Niels Grabe ; Jü ; rgen Debus ; Andreas von Deimling ; Odilia Popanda ; Christoph Plass ; Andreas Unterberg ; Amir Abdollahi ; Peter Schmezer and Christel Herold-Mende
• 刊名：International Journal of Cancer
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：139
• 期：2
• 页码：424-432
• 全文大小：492K
• ISSN：1097-0215

文摘

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. A total of 1,247 probes in 706 genes were hypermethylated in LTS and 463 probes in 305 genes were found to be hypermethylated in STS patients (p values < 0.05, log2 fold change ± 0.5). We identified 13 differentially methylated regions (DMRs) with a minimum of four 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.