DNA methylation in glioblastoma: impact on gene expression and clinical outcome

Abstract

BackgroundChanges in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies.ResultsWe performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04).ConclusionsThis study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.

The Role of Sox Transcription Factors in Brain Tumourigenesis

“…Further, Etcheverry et al has performed a wholegenome integrative analysis of methylation and gene expression profiles on GBM samples and found that the Sox10 promoter contains two hypermethylated CpG sites which are related to shorter survival. However, shorter survival time is correlated with low-expression of Sox10 in the GBM samples (Etcheverry, et al, 2010), which fits with the expression data that Sox10 is expressed to a higher extent in low grade brain tumours. We and others have not found any expression of Sox10 in medulloblastoma (Ferletta, et al, 2007;Gershon, et al, 2005).…”

The T-Box transcription factor 3 in development and cancer

“…Yamashita et al examined methylation-silenced genes in gastric cancer and revealed that the TBX3 promoter is methylated in at least one primary gastric cancer, but not normal gastric mucosa (75). TBX3 methylation was subsequently revealed to be associated with a significantly lowered survival rate in a cohort of glioblastoma patients (76). Following this, White-al Habeeb et al demonstrated that TBX3 is differentially methylated in Gleason score (GS) 8 vs GS6 prostate cancer tumour samples, with increased methylation occurring in the more aggressive GS8 samples (77).…”

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

“…These compounds have been approved by the FDA as treatments for leukemia and myelodysplastic miR-29b [80] Promote cell differentiation in muscle and tumours miR-7 [81] syndromes [103]. DNA methylation also plays an important role in glioblastoma [104] and these compounds are now also under investigation as possible therapies for these cancers. Thus, treatment of glioma cells with 5-aza-dC was able to reactivate the expression of the brain angiogenesis inhibitor (BAI1), which is normally silenced in gliomas, by recruitment of the methyl-CpG-binding domain protein 2 (MBD2) to the hypermethylated BAI1 promoter [105].…”