title: DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma.
abstract: BACKGROUND
  Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated.
  
  
  METHODS
  DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided.
  
  
  RESULTS
  We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72).
  
  
  CONCLUSIONS
  The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Smith
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
mesh_terms: D001921:Brain / Q000201:enzymology; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality*; D018899:CpG Islands; D019175:DNA Methylation; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human