Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma

Acta Neuropathol. 2014 Oct;128(4):561-71. doi: 10.1007/s00401-014-1315-x. Epub 2014 Jul 10.


The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP(pos) (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP(neg) (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP(neg) glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP(pos) tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP(pos) tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP(neg) anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain Neoplasms / classification*
  • Brain Neoplasms / genetics*
  • Chromosome Deletion
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 19 / genetics
  • CpG Islands / genetics
  • DNA Copy Number Variations / genetics*
  • DNA Helicases / genetics
  • DNA Methylation / genetics*
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Female
  • Germany
  • Glioma / classification*
  • Glioma / genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation / genetics
  • Nuclear Proteins / genetics
  • Telomerase / genetics
  • Tumor Suppressor Proteins / genetics
  • X-linked Nuclear Protein


  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • Telomerase
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein
  • DNA Repair Enzymes