Journal Article

DKFZ-2017-05262

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild-type glioblastoma patients.

Mock, A. ; Geisenberger, C. ; Orlik, C. ; Warta, R. ; Schwager, C.DKFZ* ; Jungk, C. ; Dutruel, C. ; Geiselhart, L. ; Weichenhan, D.DKFZ* ; Zucknick, M.DKFZ* ; Nied, A.-K. ; Friauf, S. ; Exner, J. ; Capper, D.DKFZ* ; Hartmann, C. ; Lahrmann, B. ; Grabe, N. ; Debus, J.DKFZ* ; von Deimling, A.DKFZ* ; Popanda, O.DKFZ* ; Plass, C.DKFZ* ; Unterberg, A. ; Abdollahi, A.DKFZ* ; Schmezer, P.DKFZ* ; Herold-Mende, C.

2016
Wiley-Liss Bognor Regis

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Please use a persistent id in citations: doi:10.1002/ijc.30069

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.

Keyword(s): Isocitrate Dehydrogenase ; IDH1 protein, human

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Contributing Institute(s):

1. Translationale Radioonkologie (E210)
2. Biostatistik (C060)
3. Epigenomik und Krebsrisikofaktoren (C010)
4. KKE Neuropathologie (G380)
5. KKE Strahlentherapie (E050)
6. DKTK Heidelberg (L101)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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