Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling

Int J Cancer. 2014 Oct 15;135(8):1822-31. doi: 10.1002/ijc.28836. Epub 2014 Mar 28.

Abstract

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.

Keywords: IDH1; MGMT; array-based comparative genomic hybridization; gene expression profiles; glioblastoma; integrative bioinformatics; long-term survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / mortality
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Gene Dosage
  • Gene Expression Profiling
  • Genome, Human
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / mortality
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Prospective Studies
  • Survivors
  • Transcriptome*
  • Tumor Suppressor Proteins / genetics

Substances

  • Tumor Suppressor Proteins
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes

Associated data

  • GEO/GSE53733