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Int J Cancer. 2016 Jul 15;139(2):424-32. doi: 10.1002/ijc.30069. Epub 2016 Mar 18.

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

Author information

1
Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
2
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
3
Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
5
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
7
Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
8
German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DFKZ), Heidelberg, Germany.
9
Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.
10
Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany.
11
National Center for Tumor Diseases (NCT), Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany.
12
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Abstract

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.

KEYWORDS:

G-CIMP; biomarker; brain tumor; methylation

PMID:
26934681
DOI:
10.1002/ijc.30069
[Indexed for MEDLINE]
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