title: DNA methylation profiles of long- and short-term glioblastoma survivors.
abstract: Glioblastoma (GBM) is the most common and malignant type of primary brain tumor in adults and prognosis of most GBM patients is poor. However, a small percentage of patients show a long term survival of 36 mo or longer after diagnosis. Epigenetic profiles can provide molecular markers for patient prognosis: recently, a G-CIMP positive phenotype associated with IDH1 mutations has been described for GBMs with good prognosis. In the present analysis we performed genome-wide DNA methylation profiling of short-term survivors (STS; overall survival < 1 y) and long-term survivors (LTS; overall survival > 3 y) by utilizing the HumanMethylation450K BeadChips to assess quantitative methylation at > 480,000 CpG sites. Cluster analysis has shown that a subset of LTS showed a G-CIMP positive phenotype that was tightly associated with IDH1 mutation status and was confirmed by analysis of the G-CIMP signature genes. Using high stringency criteria for differential hypermethylation between non-cancer brain and tumor samples, we identified 2,638 hypermethylated CpG loci (890 genes) in STS GBMs, 3,101 hypermethylated CpG loci (1,062 genes) in LTS (wild type IDH1) and 11,293 hypermethylated CpG loci in LTS (mutated for IDH1), reflecting the CIMP positive phenotype. The location of differentially hypermethylated CpG loci with respect to CpG content, neighborhood context and functional genomic distribution was similar in our sample set, with the majority of CpG loci residing in CpG islands and in gene promoters. Our preliminary study also identified a set of CpG loci differentially hypermethylated between STS and LTS cases, including members of the homeobox gene family (HOXD8, HOXD13 and HOXC4), the transcription factors NR2F2 and TFAP2A, and Dickkopf 2, a negative regulator of the wnt/β-catenin signaling pathway.
authors.affiliation: Centre for Rare Diseases and Personalized Medicine, Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK.
authors.forename: Thoraia
authors.initials: T
authors.lastname: Shinawi
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Hill
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Dean
authors.initials: D
authors.lastname: Gentle
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morris
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.forename: Farida
authors.initials: F
authors.lastname: Latif
mesh_terms: D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000401:mortality*; D018899:CpG Islands; D019175:DNA Methylation; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D009154:Mutation; D011379:Prognosis; D017741:Survivors
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: DNA methylation; IDH1; gliomas; long-term survivors; short-term survivors