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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 biology1,2,3. 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.

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Change history

  • 27 February 2012

    The original supplementary figures PDF was corrupted and has been replaced.

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Primary accessions

Gene Expression Omnibus

Data deposits

Data sets have been deposited in the Gene Expression Omnibus under accession number GSE30339.

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Acknowledgements

We thank A. Kayserian, K. Huberman, I. Dolgalev and S. Thomas for technical expertise. We thank C. Sawyers and E. Holland for helpful discussions. This grant was supported in part by the National Institutes of Health (R01CA154767-01) (T.A.C.), the National Cancer Institute (U54-CA143798) (I.K.M.), an Advanced Clinical Research Award in Glioma from the American Society of Clinical Oncology (I.K.M.), the Doris Duke Charitable Fund (I.K.M., T.A.C.), a National Brain Tumor Society Systems Biology Research Grant (I.K.M.), the MSKCC Brain Tumor Center (T.A.C.), the Louis Gerstner Foundation (T.A.C.), the STARR Cancer Consortium (T.A.C.) and the Sontag Foundation (T.A.C., I.K.M.).

Author information

Author notes

    • Sevin Turcan
    • , Daniel Rohle
    •  & Anuj Goenka

    These authors contributed equally to this work.

Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Sevin Turcan
    • , Daniel Rohle
    • , Anuj Goenka
    • , Logan A. Walsh
    • , Fang Fang
    • , Emrullah Yilmaz
    • , Carl Campos
    • , Armida W. M. Fabius
    • , Andrew Kaufman
    • , Olga Guryanova
    • , Ross Levine
    • , Adriana Heguy
    • , Luc G. T. Morris
    • , Jason T. Huse
    • , Ingo K. Mellinghoff
    •  & Timothy A. Chan
  2. Weill Cornell College of Medicine, New York, New York 10065, USA

    • Daniel Rohle
    • , Ingo K. Mellinghoff
    •  & Timothy A. Chan
  3. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Anuj Goenka
    •  & Timothy A. Chan
  4. Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Chao Lu
    • , Patrick S. Ward
    •  & Craig B. Thompson
  5. Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

    • Chao Lu
    •  & Patrick S. Ward
  6. Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Agnes Viale
  7. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Luc G. T. Morris
  8. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Jason T. Huse
  9. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Ingo K. Mellinghoff
  10. Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Ingo K. Mellinghoff
    •  & Timothy A. Chan

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Contributions

T.A.C., S.T., A.G. and I.K.M. designed the experiments. S.T., A.G., F.F., D.R., A.H., L.A.W., C.C., E.Y., C.L., P.S.W., A.V., J.T.H., A.W.M.F. and L.G.T.M. performed the experiments. S.T., J.T.H., A.G., F.F., A.K., A.H., E.Y., A.V., P.S.W., C.B.T., T.A.C. and I.K.M. analysed the data. D.R., O.G., R.L. and I.K.M. contributed new reagents. T.A.C., S.T., I.K.M. and A.G. wrote the paper.

Competing interests

C.B.T. is a consultant of Agios Pharmaceuticals and has a financial interest in Agios.

Corresponding authors

Correspondence to Ingo K. Mellinghoff or Timothy A. Chan.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figures 1-14 with legends. These figures show methylation profiles of parental, IDH1 wild-type and IDH1 mutant astrocytes; validation of differentially methylated regions using EpiTYPER; association of CIMP identified from lower grade gliomas with various clinical covariates; predictive power of the 17-gene signature on the MSKCC cohort and the Rembrandt validation dataset; promotion of a neurosphere phenotype in human astrocytes upon mutant IDH1 expression. The original file posted on line was corrupted and was replaced on 27 February 2012.

Zip files

  1. 1.

    Supplementary Tables 1-17

    Table 1 shows the differentially methylated genes at passage 40 in IDH1 R132H expressing human astrocytes.  Table 2 shows the differentially expressed genes at passage 40 in IDH1 R132H expressing human astrocytes.  Table 3 shows the enrichment of PANTHER pathways and biological processes in differentially expressed genes at passage 40 in mutant IDH1 expressing human astrocytes.  Table 4 includes the enriched literature defined Oncomine concepts in mutant IDH1 expressing human astrocytes.  Table 5 includes the patient characteristics for the MSKCC Cohort used for methylation and expression screens (MS Excel spreadsheet; 49 KB).  Table 6 shows the differentially methylated genes between CIMP groups in MSKCC cohort of lower grade glioma samples (MS Excel spreadsheet; 9.9 MB).  Table 7 shows the enriched gene sets and PRC2 targets as identified by GSEA in CIMP+ tumors.  Table 8 shows the differentially expressed genes in CIMP tumors.  Table 9 shows the PANTHER ontology terms enriched in the differentially expressed genes in CIMP tumors.  Table 10 shows the multivariate analysis of predictors of CIMP in MSKCC Cohort.  Table 11 shows the multivariate analysis of survival in lower grade gliomas (MS Word document 156 KB).  Table 12 shows the hypermethylated and downregulated genes in CIMP positive tumors.  Table 13 shows the hypermethylated probes used for GSEA.  Table 14 shows the differentially methylated probes from IDH1 expressing human astrocytes used to classify CIMP tumors from MSKCC cohort.  Table 15 shows the 17 gene signature derived from clinical and cell line data used to classify TCGA samples.  Table 16 shows the multivariate analysis of predictors of survival in Rembrandt validation data set.  Table 17 shows the EpiTYPER primers used for validation of methylated genes in IDH1 expressing astrocytes and LGG tumors.

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DOI

https://doi.org/10.1038/nature10866

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