IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype Journal Article


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.
Article Title: 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 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. © 2012 Macmillan Publishers Limited. All rights reserved.
Journal Title: Nature
Volume: 483
Issue: 7390
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2012-02-15
Start Page: 479
End Page: 483
Language: English
DOI: 10.1038/nature10866
PROVIDER: scopus
PUBMED: 22343889
PMCID: PMC3351699
DOI/URL:
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 2 April 2012" - "CODEN: NATUA" - "Source: Scopus"
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MSK Authors
  1. Adriana Heguy
    88 Heguy
  2. Timothy Chan
    317 Chan
  3. Emrullah Yilmaz
    2 Yilmaz
  4. Anuj Goenka
    18 Goenka
  5. Luc Morris
    281 Morris
  6. Ross Levine
    782 Levine
  7. Jason T Huse
    143 Huse
  8. Agnes Viale
    245 Viale
  9. Armida Wanda Mathilde Fabius
    13 Fabius
  10. Fang Fang
    6 Fang
  11. Sevin Turcan
    25 Turcan
  12. Chao Lu
    19 Lu
  13. Patrick Shea Ward
    16 Ward
  14. Logan Alexander Walsh
    19 Walsh
  15. Daniel A Rohle
    14 Rohle
  16. Carl Campos
    37 Campos
  17. Craig Bernie Thompson
    155 Thompson