Article
DNA methylation profiles of long- and short-term glioblastoma survivors
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Published: | May 21, 2013 |
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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.