Article
Global analysis of the glioblastoma epigenome identifies different major classes of epigenetically-regulated genes
Search Medline for
Authors
Published: | May 20, 2009 |
---|
Outline
Text
Objective: Molecular investigation of glioblastoma multiforme has indicated a significant, increasing role for epigenetic events in the pathogenesis of this malignancy. To assess the glioblastoma epigenome more comprehensively, we have undertaken a genome-wide investigation to identify genes which display evidence of methylation-dependent regulation.
Methods: 90 consecutive glioblastoma patients were investigated. All patients had undergone surgery and adjuvant therapy. DNA methylation profiling was performed using methylation bead arrays. Methylation was assessed at 1.536 CpG sites in 371 genes (one to nine sites per gene). The amount of bisulfite-modified target DNA that hybridizes to each spot of the chip was quantified and standardized to a maximum of 1.0 (the likelihood of hypermethylation of this gene promoter is almost 100%) and a minimum of 0.0 (the likelihood of promoter hypermethylation is almost 0%). The assay was validated by analyzing normal brain tissue and the glioblastoma tumor cell line U87.
Results: The median age at diagnosis was 60.72 years (range: 52.6–70.3; SD: 8.8). The median survival time after surgery was 9.6 months (range: 3.0–93.6; SD: 15.84). We have observed different major classes of epigenetically regulated genes in tumor tissue: a) normally methylated genes whose methylation reflects somatic patterns observed in the cerebrum; b) genes showing loss of methylation as a consequence of a global tumor demethylation (n= 21); c) tumor specific methylated genes which display enhanced methylation levels compared to the normal brain tissue (n=12).
Conclusions: Our data reveal a more diverse and expansive glioblastoma epigenome than previously understood and provide strong evidence that the methylation status of specific genes is of major relevance in GBM pathogenesis.