TY  - JOUR
AU  - Mock, Andreas
AU  - Geisenberger, Christoph
AU  - Orlik, Christian
AU  - Warta, Rolf
AU  - Schwager, Christian
AU  - Jungk, Christine
AU  - Dutruel, Céline
AU  - Geiselhart, Lea
AU  - Weichenhan, Dieter
AU  - Zucknick, Manuela
AU  - Nied, Ann-Katrin
AU  - Friauf, Sara
AU  - Exner, Janina
AU  - Capper, David
AU  - Hartmann, Christian
AU  - Lahrmann, Bernd
AU  - Grabe, Niels
AU  - Debus, Jürgen
AU  - von Deimling, Andreas
AU  - Popanda, Odilia
AU  - Plass, Christoph
AU  - Unterberg, Andreas
AU  - Abdollahi, Amir
AU  - Schmezer, Peter
AU  - Herold-Mende, Christel
TI  - LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild-type glioblastoma patients.
JO  - International journal of cancer
VL  - 139
IS  - 2
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2017-05262
SP  - 424 - 432
PY  - 2016
AB  - 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.
KW  - Isocitrate Dehydrogenase (NLM Chemicals)
KW  - IDH1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26934681
DO  - DOI:10.1002/ijc.30069
UR  - https://inrepo02.dkfz.de/record/130182
ER  -