Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Jonathan D. Buckley, Li Ding, Fei Pan, Leslie Cope, Christopher E. Pelloski, Kristin Diefes, Katherine A. Hoadley, Benjamin P. Berman, Stephen B. Baylin, Peter W. Laird, Hui Shen, Kanan Pujara, Roel G.W. Verhaak, Henrik Bengtsson, Daniel J. Weisenberger, David Van Den Berg, Heather K. Schmidt, Krishna Bhat, Charles M. Perou, D Neil Hayes, Richard K. Wilson, James G. Herman, Houtan Noushmehr, Erik P. Sulman, Kenneth Aldape, Pierre Neuvial, Heidi Phillips
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 low-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.