IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype

By Şevin Turcan, D. Rohle, A. Goenka, L. Walsh, F. Fang, E. Yilmaz, Carl Campos, A. Fabius, Chao Lu, Patrick S. Ward and 10 more. Nature, 2012

1,888 citations recorded by the source corpus.

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 biology. 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d63703eaf638e0f11509344b460342ac8d99cb0c

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Citations in the corpus

Targeting Metabolism for Cancer Therapy (2017, positive): “Disclosures M.G.V.H. is a consultant and Scientific Advisory Board member for Agios Pharmaceuticals and Aeglea Biotherapeutics. uthor M anuscript A uthor M anuscript A uthor M anuscript nucleotides for DNA synthesis (Figure 1b, Figure 2c).”
Lessons from the cancer genome. (2013, neutral): “A follow-up study confirmed that introduction of mutant IDH actually caused the CIMP-like phenotype (Turcan et al., 2012).”
The Warburg Effect Dictates the Mechanism of Butyrate Mediated Histone Acetylation and Cell Proliferation (2012, positive): “This idea is supported by recent reports showing that the oncometabolite 2-hydroxyglutarate, which accumulates in tumors as a result of isocitrate dehydrogenase (IDH1/2) mutations, inhibits JmjC histone demethylases and DNA methyltransferses to alter the transcription of genes necessary for differen”
Glioma Subclassifications and Their Clinical Significance (2017, neutral): “likely other contributing mechanisms [16, 17].”
Metabolic regulation of epigenetics (2012, positive): “Indeed, glioma samples with IDH mutations displayed higher levels of H3K9me3 and H3K27me3.”
Genetics of adult glioma. (2012, positive): “Using in vitro model systems, recent studies have shown that IDH mutation impairs histone demethylation, resulting in widespread promoter hypermethylation (31,32).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “In contrast, multiple groups have found that IDH mutant expression and 2HG elevation can inhibit the TET family of enzymes that hydroxylate 50-methylcytosine (Figueroa et al., 2010; Turcan et al., 2012; Xu et al., 2011). a-ketoglutaratedependent TET activity produces 50-hydroxymethylcytosine.”
Mitochondria: In Sickness and in Health (2012, positive): “Recent intriguing findings in gliomas indicated that IDH1 mutations contribute to gliomas via multiple mechanisms, including stabilizing hypoxia-inducible factor 1, as was previously found in other tumorigenic TCA defects, and by altering the methylation of CpG islands and histones, which causes wid”
Epigenetic Determinants of Cancer. (2016, positive): “…gliomas Mutation/silencing (Araki et al. 2009) IDH1/2 Isocitrate dehydrogenase Glioma, AML Mutation (Figueroa et al. 2010; Lu et al. 2012; Turcan et al. 2012) AID 5′-Cytidine deaminase CML Aberrant expression (De Carvalho et al. 2010) MLL1/2/3 Histone methyltransferase H3K4 Bladder…”