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IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Open accessAbstract
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.
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“IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, though the functional significance of this altered epigenetic state remains unclear.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [11]
In the citing paper
“As a result, D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA (Figueroa et al., 2010; Lu et al., 2012; Turcan et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Turcan et al., 2012
In the citing paper
“Specifically, owing to the interference with TET family proteins, the mutation causes the CpG island methylator phenotype116,123.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [123]
In the citing paper
“Indeed, IDH-driven gliomas, leukemias and chondrosarcomas display a prominent CpG island hypermethylation, reminiscent of the hypermethylator phenotype seen in SDH- and FH-deficient cancers (Figueroa et al., 2010; Lu et al., 2013; Turcan et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Turcan et al., 2012
In the citing paper
“In the cancer setting, 2-HG has been shown to influence a number of biological processes, including cell differentiation, DNA methylation, and histone methylation (79–82), leading to its classification as an oncometabolite.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [82]
In the citing paper
“Like TH17 cells, CD8+ T cells are highly dependent on the activation of HIF-1α and glycolysis, which is responsible for mediating trafficking into hypoxic tumour environments and inflamed tissue147,148.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [147]
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Metadata
- Authors
- Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., Campos, C., Fabius, A. W. M., Lu, C., Ward, P. S., Thompson, C. B., Kaufman, A., Guryanova, O., Levine, R., Heguy, A., Viale, A., Morris, L. G. T., Huse, J. T., Mellinghoff, I. K., & Chan, T. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Mellinghoff, Ingo K.
- Chan, Timothy A.
- ORCID
- Venue
- Nature
- Published
- 2012-02-15
- Volume
- 483
- Issue
- 7390
- Pages
- 479-483
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3351699
- OpenAlex
- W1988756388
- Cited by
- 1,974
- References
- 44
- Citations by year
- 2026: 90 · 2025: 92 · 2024: 104 · 2023: 100 · 2022: 136 · 2021: 148 · 2020: 140 · 2019: 142 · 2018: 169 · 2017: 144 · 2016: 163 · 2015: 154 · 2014: 153 · 2013: 152 · 2012: 83
- FWCI
- 82.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (F31CA260794, R01CA154767, U54CA143798, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, glioma, CpG island methylator phenotype, DNA hypermethylation, 2-hydroxyglutarate, oncometabolites, histone demethylation, methylome, astrocytes, gliomagenesis, hypoxia-inducible factor, epigenetic reprogramming
- MeSH terms
- Astrocytes, Cell Survival, Cells, Cultured, Gene Expression Regulation, Glioblastoma, Glioma, Histones, Humans, Isocitrate Dehydrogenase, Mutation, Phenotype, Tumor Cells, Cultured, CpG Islands, DNA Methylation, Epigenesis, Genetic, Metabolome, HEK293 Cells, Epigenomics
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