Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma

Houtan Noushmehr, Daniel J. Weisenberger, Kristin Diefes, Heidi S. Phillips, Kanan Pujara, Benjamin P. Berman, Fei Pan, Christopher E. Pelloski, Erik P. Sulman, Krishna P. Bhat, Roel G.W. Verhaak, Katherine A. Hoadley, D. Neil Hayes, Charles M. Perou, Heather K. Schmidt, Li Ding, Richard K. Wilson, David Van Den Berg, Hui Shen, Henrik BengtssonPierre Neuvial, Leslie M. Cope, Jonathan Buckley, James G. Herman, Stephen B. Baylin, Peter W. Laird*, Kenneth Aldape

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1892 Scopus citations

Abstract

We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.

Original languageAmerican English
Pages (from-to)510-522
Number of pages13
JournalCancer Cell
Volume17
Issue number5
DOIs
StatePublished - 18 May 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by NIH/NCI grants U24 CA126561 and U24 CA143882-01 (P.W.L. and S.B.B.), grants from the M.D. Anderson Center for Cancer Epigenetics, the Brain Tumor Funders' Collaborative, the V Foundation, and the Rose Foundation, and SPORE grant P50CA127001 from NIH/NCI (K.A.). We thank Dennis Maglinte and members of the USC Epigenome Center for helpful discussions, Andreana Rivera for technical assistance, and Marisol Guerrero for editorial assistance. P.W.L. is a shareholder, consultant, and scientific advisory board member of Epigenomics, AG, which has a commercial interest in DNA methylation markers. This work was not supported by Epigenomics, AG. K.A. is a consultant and scientific advisory board member for Castle Biosciences, which has a commercial interest in molecular diagnostics. This work was not supported by Castle Biosciences.

Keywords

  • CELLCYCLE
  • DNA
  • HUMDISEASE

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