title: LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild-type glioblastoma patients.
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.
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.|Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.|Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mock
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Geisenberger
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Orlik
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Warta
authors.affiliation: Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwager
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Jungk
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Céline
authors.initials: C
authors.lastname: Dutruel
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Geiselhart
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Nied
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Friauf
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Exner
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany.|Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Odilia
authors.initials: O
authors.lastname: Popanda
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.affiliation: Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DFKZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D059248:Chemoradiotherapy; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: G-CIMP; biomarker; brain tumor; methylation