Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma

Abstract

The study of survival outliers of glioblastoma (GBM) can have important implications on gliomagenesis as well as in the identification of ways to alter clinical course on this almost uniformly lethal cancer type. However, current studied epigenetic and genetic signatures of the GBM outliers have failed to identify unifying criteria to characterize this unique group of patients. In this study, we profiled the global DNA methylation pattern of mainly IDH1 wild type survival outliers of glioblastoma and performed comprehensive enrichment analyses with genomic and epigenomic signatures. We found that the genome of long-term survivors in glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. The hypomethylation pattern at the region distant from CGI is associated with lower rates of de novo mutations while the hypermethylation at CGIs correlates with transcriptional downregulation of genes involved in cancer progression pathways. These results extend our understanding of DNA methylation of survival outliers in glioblastoma in a genome-wide level, and provide insight on the potential impact of DNA hypomethylation in cancer genome.