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Mock, Andreas; Geisenberger, Christoph; Orlik, Christian; Warta, Rolf; Schwager, Christian; Jungk, Christine; Dutruel, Céline; Geiselhart, Lea; Weichenhan, Dieter; Zucknick, Manuela; Nied, Ann‐Katrin; Friauf, Sara; Exner, Janina; Capper, David; Hartmann, Christian; Lahrmann, Bernd; Grabe, Niels; Debus, Jürgen; von Deimling, Andreas; Popanda, Odilia; Plass, Christoph; Unterberg, Andreas; Abdollahi, Amir; Schmezer, Peter;

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

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  • Media type: E-Article
  • Title: LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild‐type glioblastoma patients
  • Contributor: Mock, Andreas; Geisenberger, Christoph; Orlik, Christian; Warta, Rolf; Schwager, Christian; Jungk, Christine; Dutruel, Céline; Geiselhart, Lea; Weichenhan, Dieter; Zucknick, Manuela; Nied, Ann‐Katrin; Friauf, Sara; Exner, Janina; Capper, David; Hartmann, Christian; Lahrmann, Bernd; Grabe, Niels; Debus, Jürgen; von Deimling, Andreas; Popanda, Odilia; Plass, Christoph; Unterberg, Andreas; Abdollahi, Amir; Schmezer, Peter;
  • imprint: Wiley, 2016
  • Published in: International Journal of Cancer
  • Language: English
  • DOI: 10.1002/ijc.30069
  • ISSN: 0020-7136; 1097-0215
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:p><jats:italic>MGMT</jats:italic> promoter methylation status is currently the only established molecular prognosticator in <jats:italic>IDH</jats:italic> 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; &gt;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 (<jats:italic>p</jats:italic> values &lt; 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 (<jats:italic>ADCY1</jats:italic>, <jats:italic>GPC3</jats:italic>, <jats:italic>LOC283731/ISLR2</jats:italic>). These DMRs were further assessed for their prognostic capability in an independent validation cohort (<jats:italic>n</jats:italic> = 62) of non‐G‐CIMP GBMs from the TCGA. Hypermethylation of multiple CpGs mapping to the promoter region of <jats:italic>LOC283731</jats:italic> correlated with improved patient outcome (<jats:italic>p</jats:italic> = 0.03). The prognostic performance of <jats:italic>LOC283731</jats:italic> promoter hypermethylation was confirmed in a third independent study cohort (<jats:italic>n</jats:italic> = 89), and was independent of gender, performance (KPS) and <jats:italic>MGMT</jats:italic> status (<jats:italic>p</jats:italic> = 0.0485, HR = 0.63). Intriguingly, the prediction was most pronounced in younger GBM patients (&lt;60 years). In conclusion, we provide compelling evidence that promoter methylation status of this novel gene is a prognostic biomarker in <jats:italic>IDH1</jats:italic> wild‐type/non‐G‐CIMP GBMs.</jats:p>
  • Access State: Open Access