Epigenetic Changes in Gliomas

Abstract

Epigenetic alterations have been fundamentally implicated in the pathobiology of several malignancies including gliomas. Such changes involve tumor specific promoter methylation, histone modifications, and changes in microRNA. Several such recently reported alterations have also been seen to highly correlate with outcome highlighting their clinical significance, including the following: Promoter methylation of MGMT correlates with improved survival in glioblastoma patients who receive chemoradiation therapy and in anaplastic glioma patients treated with radiation alone as frontline therapy. A glioma CpG island methylator phenotype (G-CIMP) confers better survival to patients with the proneural subtype of glioblastoma. Mutations of IDH1 are commonly seen as early events in low grade and anaplastic gliomas and are also associated with a hypermethylator phenotype. Mutations of H3F3A which encodes the histone variant H3.3 have been reported in pediatric high grade gliomas which in turn have been linked to reduction in the histone H3 lysine trimethylation mark (H3K27me3) and possibly DNA hypomethylation as mechanisms for activated gene expression. Lastly, altered expression of several microRNA has been implicated in glioma biology. These findings point to a rapidly expanding recognition of the critical role of epigenetic changes in gliomagenesis and pathobiology. This in turn has given rise to clinical trials that either utilize epigenetic alterations as prognostic markers for patient stratification or in attempts at therapeutic targeting of epigenetic states of gliomas. However, much remains to be learned about the complex interplay between various epigenetic factors in glioma cells and their influence on genetic alterations; such insights will provide a foundation for therapeutic strategies aimed at modulating epigenetic factors to target high and low grade gliomas.