gms | German Medical Science

64th Annual Meeting of the German Society of Neurosurgery (DGNC)

German Society of Neurosurgery (DGNC)

26 - 29 May 2013, Düsseldorf

DNA methylation profiles of long- and short-term glioblastoma survivors

Meeting Abstract

  • Dietmar Krex - Department of Neurosurgery, University Hospital Dresden, Dresden, Germany
  • Thoraia Shinawi - Centre for Rare Diseases and Personalized Medicine and Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, United Kingdom
  • Victoria Hill - Centre for Rare Diseases and Personalized Medicine and Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, United Kingdom
  • Gabriele Schackert - Department of Neurosurgery, University Hospital Dresden, Dresden, Germany
  • Dean Gentle - Centre for Rare Diseases and Personalized Medicine and Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, United Kingdom
  • Wenbin Wei - School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
  • Eamonn R. Maher - Centre for Rare Diseases and Personalized Medicine and Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, United Kingdom
  • Farida Latif - Centre for Rare Diseases and Personalized Medicine and Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, United Kingdom

Deutsche Gesellschaft für Neurochirurgie. 64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC). Düsseldorf, 26.-29.05.2013. Düsseldorf: German Medical Science GMS Publishing House; 2013. DocP 136

doi: 10.3205/13dgnc553, urn:nbn:de:0183-13dgnc5539

Published: May 21, 2013

© 2013 Krex et al.
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Outline

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Objective: Median survival of patients with glioblastoma (GBM), the most common and malignant type of primary brain tumor, is 12 to 14 months. However, a small percentage of patients show long-term survival of 36 months or longer after diagnosis. Epigenetic profiles can provide molecular markers for patient prognosis. Recently, a G-CIMP phenotype associated with IDH1 mutations has been described for GBMs with good prognosis. In the present study we analyzed whether short-term survivors (STS) differ from long-term survivors (LTS) in their epigenetic profile.

Method: Glioblastoma patients with survival of less than 12 months and longer than 36 months, respectively, were identified out of our local tumor-data-bank. We performed genome-wide DNA methylation profiling by utilizing the HumanMethylation450K BeadChips to assess quantitative methylation at >480,000 CpG sites. Clone sequencing was used for array validation. Differential methylation was assessed by various statistical procedures. IDH-mutation status was determined by sequencing.

Results: Cluster analysis showed that a subset of LTS demonstrated a G-CIMP phenotype that was tightly associated with IDH1 mutation status and was confirmed by analysis of the G-CIMP signature genes (Noushmehr et al 2010). Using high stringency criteria for differential hypermethylation between non-cancer brain and tumor samples we identified 2638 (890 genes) hypermethylated CpG loci in STS GBMs and 3101 (1062 genes) hypermethylated CpG loci in LTS (wt IDH1) and a much larger number in LTS with IDH1 mutations (11293 loci; 3323 genes) reflecting the CIMP phenotype. In addition we identified a set of probes/genes that showed differential hypermethylation between STS and LTS cases (P<0.05) and were associated with unfavourable patient survival. Amongst these genes were members of the homeobox gene family (HOXD8, HOXD13, HOXC4), and the transcription factors NR2F2 and TFAP2A.

Conclusions: We determined the methylomes of short- and long-term glioblastoma survivors using the latest high density methylation beadchips. A set of CpG loci that show differential hypermethylation in STS compared to LTS gliomas was identified, and a tight association of CIMP+ with IDH1 mutations in a subset of LTS was found.