IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype

Abstract

Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology1–3. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Since 2-hydroxyglutarate is an endpoint metabolite that is not further converted, it rapidly accumulates in the cells and outcompetes the structurally similar α-ketoglutarate as a cofactor for α-ketoglutarate-dependent dioxygenases [204,205]. This leads to an inhibition of the α-ketoglutarate-dependent dioxygenases and consequently to histone hypermethylation [206]. The altered methylation patterns thereby promote dedifferentiation of the tumors.…”

Genetic alterations of IDH1 and Vegf in brain tumors

“…These dioxygenases are thought to be involved in epigenetic control, suggesting that mutations in  IDH1  can affect a large number of genes (Watanabe, Nobusawa, Kleihues, & Ohgaki, 2009; Zhao et al., 2009). IDH1 mutations are likely to be a direct cancer driver in early stage of gliomagenesis promoting extensive alteration of the epigenetic pattern (Turcan et al., 2012; Watanabe et al., 2009). …”

Molecular Investigation of Isocitrate Dehydrogenase Gene (IDH) Mutations in Gliomas: First Report of IDH2 Mutations in Indian Patients

“…Several theories have been proposed, Turcan et al (2012) reported that IDH mutations induces extensive DNA hypermethylation by remodeling the methylome to establish glioma hypermethylator phenotype which results in reorganization of the methylome and transcriptome (Turcan et al, 2012). In addition to this, it is also thought that IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate and confer novel enzymatic activity, facilitating the reduction of α-ketoglutarate to Table 2 2-hydroxyglutarate, a putative oncometabolite (Koivunen et al, 2012;Losman et al, 2013) and therefore IDH1 and IDH2 mutations are likely the integrally involved in the pathogenesis of malignant transformation (i.e., driver mutations) rather than epiphenomena.…”