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. 2013 Feb;8(2):149-56.
doi: 10.4161/epi.23398. Epub 2013 Jan 4.

VSports在线直播 - DNA methylation profiles of long- and short-term glioblastoma survivors

Thoraia Shinawi  1 , Victoria K Hill, Dietmar Krex, Gabriele Schackert, Dean Gentle, Mark R Morris, Wenbin Wei, Garth Cruickshank, Eamonn R Maher, Farida Latif
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VSports在线直播 - DNA methylation profiles of long- and short-term glioblastoma survivors

Thoraia Shinawi et al. Epigenetics. 2013 Feb.

V体育官网入口 - Abstract

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor in adults and prognosis of most GBM patients is poor VSports手机版. 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. .

Keywords: DNA methylation; IDH1; gliomas; long-term survivors; short-term survivors. V体育安卓版.

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V体育官网 - Figures

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Figure 1. Validation of probe β value using bisulfite clone sequencing. Individual samples were tested with high or with low β values for each of the 4 genes, HOXA3, SLIT2, FZD9 and RASSF1A. For each sample and loci, the β value is given and the methylation index (MI) was calculated using the formula, number of CpG dinucleotides methylated/total number of CpG dinucleotides sequenced × 100. Black circles represent methylation of the CpG loci and white circles represent unmethylated loci.
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Figure 2. Unsupervised clustering of the 500 most variable CpG loci identifies CIMP+ phenotype in 5 LTS tumors. CpG loci are color coded from white (low methylation) to black (hypermethylation). The bar below the figure indicates CIMP status (black, CIMP+; white, CIMP-), IDH mutation (black, mutated; white, wild-type), MGMT methylation (black, methylated; white, unmethylated; crossed, undetermined), and type of glioma (white, STS; black, LTS).
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Figure 3. Description of the methylome of the 3 groups of glioma in the (A) hypermethylated, (B) hypomethylated CpG loci. Functional genomic distribution: body, 3′UTR, intergenic and promoter region (i). CpG content and neighborhood context classification: island, shore, shelf and open sea (ii).
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Figure 4. Top two gene networks generated from Ingenuity analysis of the STS vs. LTS differentially hypermethylated genes. Of the 23 STS differentially hypermethylated genes, 18 genes fell within these two networks. Methylated genes are shaded gray, while the necessary connecting genes are unshaded.
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