Dataset Information

Isocitrate dehydrogenase 1 (IDH1) mutant gliomas demonstrate a distinct global CpG island methylation profile compared to IDH1 wildtype gliomas using MRSE

ABSTRACT: In order to identify other molecular aberrations that may cooperate with IDH1R132MUT in gliomagenesis, we performed CpG-island methylation profiling analysis using MSRE (Tran et al. Front. Neurosci. 3:57. Doi: 10.3389/neuro.15.005.2009) on a subset of IDH1R132MUT and IDH1R132WT GBMs and found a distinct pattern of CpG island hypermethylation that was detected in all GBMs and lower grade gliomas with IDH1R132MUT. While absent from nearly all IDH1R132WT glioma, the methylation pattern in IDH1R132MUT GBMs shows similarity to the recently reported CpG island methylator phenotype (CIMP) found to be tightly associated with IDH1R132MUT gliomas(Noushmehr et al. Cancer Cell, Volume 17, Issue 5, 18 May 2010, Pages 510-522, ISSN 1535-6108, DOI: 10.1016/j.ccr.2010.03.017). Methylation profiling performed on 40 distinct brain tumor samples: 7 Anaplastic Astrocytomas, including 3 IDH1MUT and 4 IDH1WT; 5 Lowgrade Astrocytomas, including 4 IDH1MUT and 1 IDH1WT; 28 Glioblastoma, including 8 IDH1MUT and 20 IDH1WT.

ORGANISM(S): Homo sapiens

SUBMITTER: Reshmi Chowdhury Albert Lai

PROVIDER: E-GEOD-28271 | ArrayExpress | 2011-10-24

SECONDARY ACCESSION(S): GSE28271PRJNA139265

REPOSITORIES: GEO, ArrayExpress

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Publications

In Silico Enhanced Restriction Enzyme Based Methylation Analysis of the Human Glioblastoma Genome Using Agilent 244K CpG Island Microarrays.

Tran Anh A Escovedo Cameron C Migdall-Wilson Justine J Chou Arthur P AP Chen Weidong W Cloughesy Timothy T Nelson Stanley S Lai Albert A

Frontiers in neuroscience 20090101

Genome wide methylation profiling of gliomas is likely to provide important clues to improving treatment outcomes. Restriction enzyme based approaches have been widely utilized for methylation profiling of cancer genomes and will continue to have importance in combination with higher density microarrays. With the availability of the human genome sequence and microarray probe sequences, these approaches can be readily characterized and optimized via in silico modeling. We adapted the previously d ...[more]

PMID: 20582289

Publication: 1/2

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Project description:Glioblastoma multiformes (GBMs) are high-grade astrocytomas and the most common brain malignancies. Primary GBMs are often associated with disturbed RAS signaling, and expression of oncogenic HRAS results in a malignant phenotype in glioma cell lines. Secondary GBMs arise from lower-grade astrocytomas, have slower progression than primary tumors, and contain IDH1 mutations in over 70% of cases. Despite significant amount of accumulating genomic and transcriptomic data, the fundamental mechanistic differences of gliomagenesis in these two types of high-grade astrocytoma remain poorly understood. Only a few studies have attempted to investigate the proteome, phosphorylation signaling, and epigenetic regulation in astrocytoma. In the present study, we applied quantitative phosphoproteomics to identify the main signaling differences between oncogenic HRAS and mutant IDH1-driven glioma cells as models of primary and secondary GBM, respectively. Our analysis confirms the driving roles of the MAPK and PI3K/mTOR signaling pathways in HRAS driven cells and additionally uncovers dysregulation of other signaling pathways. Although a subset of the signaling changes mediated by HRAS could be reversed by a MEK inhibitor, dual inhibition of MEK and PI3K resulted in more complete reversal of the phosphorylation patterns produced by HRAS expression. In contrast, cells expressing mutant IDH1 did not show significant activation of MAPK or PI3K/mTOR pathways. Instead, global downregulation of protein expression was observed. Targeted proteomic analysis of histone modifications identified significant histone methylation, acetylation, and butyrylation changes in the mutant IDH1 expressing cells, consistent with a global transcriptional repressive state. Our findings offer novel mechanistic insight linking mutant IDH1 associated inhibition of histone demethylases with specific histone modification changes to produce global transcriptional repression in secondary glioblastoma. Our proteomic datasets are available for download and provide a comprehensive catalogue of alterations in protein abundance, phosphorylation, and histone modifications in oncogenic HRAS and IDH1 driven astrocytoma cells beyond the transcriptomic level.