Unraveling the glioma epigenome: from molecular mechanisms to novel biomarkers and therapeutic targets.

Epigenetic regulation of gene expression by DNA methylation and histone modification is frequently altered in human cancers including gliomas, the most common primary brain tumors. In diffuse astrocytic and oligodendroglial gliomas, epigenetic changes often present as aberrant hypermethylation of 5'-cytosine-guanine (CpG)-rich regulatory sequences in a large variety of genes, a phenomenon referred to as glioma CpG island methylator phenotype (G-CIMP). G-CIMP is particularly common but not restricted to gliomas with isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) mutation. Recent studies provided a mechanistic link between these genetic mutations and the associated widespread epigenetic modifications. Specifically, 2-hydroxyglutarate, the oncometabolite produced by mutant IDH1 and IDH2 proteins, has been shown to function as a competitive inhibitor of various α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases and members of the ten-eleven-translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. In this review article, we briefly address (i) the basic principles of epigenetic control of gene expression; (ii) the most important methods to analyze focal and global epigenetic alterations in cells and tissues; and (iii) the involvement of epigenetic alterations in the molecular pathogenesis of gliomas. Moreover, we discuss the promising roles of epigenetic alterations as molecular diagnostic markers and novel therapeutic targets, and highlight future perspectives toward unraveling the "glioma epigenome."