title: Stability of the CpG island methylator phenotype during glioma progression and identification of methylated loci in secondary glioblastomas.
abstract: BACKGROUND
  Grade IV glioblastomas exist in two forms, primary (de novo) glioblastomas (pGBM) that arise without precursor lesions, and the less common secondary glioblastomas (sGBM) which develop from earlier lower grade lesions. Genetic heterogeneity between pGBM and sGBM has been documented as have differences in the methylation of individual genes. A hypermethylator phenotype in grade IV GBMs is now well documented however there has been little comparison between global methylation profiles of pGBM and sGBM samples or of methylation profiles between paired early and late sGBM samples.
  
  
  METHODS
  We performed genome-wide methylation profiling of 20 matched pairs of early and late gliomas using the Infinium HumanMethylation450 BeadChips to assess methylation at >485,000 cytosine positions within the human genome.
  
  
  RESULTS
  Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors. In 80% of cases, the hypermethylator status was retained in both the early and late tumor of the same patient, indicating limited alterations to genome-wide methylation during progression and that the CIMP phenotype is an early event. Analysis of hypermethylated loci identified 218 genes frequently methylated across grade II, III and IV tumors indicating a possible role in sGBM tumorigenesis. Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles. We also identified 180 genes that were methylated only in sGBM. Further analysis of these genes may lead to a better understanding of the pathology of sGBM vs pGBM.
  
  
  CONCLUSIONS
  This is the first study to have documented genome-wide methylation changes within paired early/late astrocytic gliomas on such a large CpG probe set, revealing a number of genes that maybe relevant to secondary gliomagenesis.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Hill
authors.forename: Thoraia
authors.initials: T
authors.lastname: Shinawi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Julien
authors.initials: J
authors.lastname: Bauer
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.forename: Garth
authors.initials: G
authors.lastname: Cruickshank
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.affiliation: Centre for Rare Diseases and Personalised Medicine and Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, UK. f.latif@bham.ac.uk.
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D010641:Phenotype
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human