title: A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951.
abstract: OBJECTIVE
  The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas.
  
  
  METHODS
  To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive.
  
  
  RESULTS
  Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP(+)) subgroup was markedly better than the survival of the unmethylated (CIMP(-)) subgroup (5.62 vs. 1.24 years; P < 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA).
  
  
  CONCLUSIONS
  The strong association between CIMP status and MGMT promoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis.
authors.affiliation: Neuro-Oncology Unit, Department of Neurology, Daniel den Hoed Cancer Center/Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Lonneke A
authors.initials: LA
authors.lastname: Gravendeel
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Lariesa
authors.initials: L
authors.lastname: Lapre
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Teepen
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.forename: Peter A E Sillevis
authors.initials: PA
authors.lastname: Smitt
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009837:Oligodendroglioma / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes