Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma

Abstract

BackgroundGlioblastoma arises from complex interactions between a variety of genetic alterations and environmental perturbations. Little attention has been paid to understanding how genetic variations, altered gene expression and microRNA (miRNA) expression are integrated into networks which act together to alter regulation and finally lead to the emergence of complex phenotypes and glioblastoma.ResultsWe identified association of somatic mutations in 14 genes with glioblastoma, of which 8 genes are newly identified, and association of loss of heterozygosity (LOH) is identified in 11 genes with glioblastoma, of which 9 genes are newly discovered. By gene coexpression network analysis, we indentified 15 genes essential to the function of the network, most of which are cancer related genes. We also constructed miRNA coexpression networks and found 19 important miRNAs of which 3 were significantly related to glioblastoma patients' survival. We identified 3,953 predicted miRNA-mRNA pairs, of which 14 were previously verified by experiments in other groups. Using pathway enrichment analysis we also found that the genes in the target network of the top 19 important miRNAs were mainly involved in cancer related signaling pathways, synaptic transmission and nervous systems processes. Finally, we developed new methods to decipher the pathway connecting mutations, expression information and glioblastoma. We indentified 4 cis-expression quantitative trait locus (eQTL): TP53, EGFR, NF1 and PIK3C2G; 262 trans eQTL and 26 trans miRNA eQTL for somatic mutation; 2 cis-eQTL: NRAP and EGFR; 409 trans- eQTL and 27 trans- miRNA eQTL for lost of heterozygosity (LOH) mutation.ConclusionsOur results demonstrate that integrated analysis of multi-dimensional data has the potential to unravel the mechanism of tumor initiation and progression.

LC-MS/MS Analysis of Differentially Expressed Glioblastoma Membrane Proteome Reveals Altered Calcium Signaling and Other Protein Groups of Regulatory Functions

“…Seven proteins (ANXA2, XRCC6, SCARB2, GOLIM4, CAMKIIA, RAB3A, and SV2A) were thus selected, and IHC was performed with six individual cases. Comparison with the primary transcriptome data published by TCGA Network supports altered expression of these proteins (6). Other differentially expressed proteins such as atlastin 3 (ATL3), paralemmin 2 (PALM2), and neuronal growth regulator 1 (NEGR1), which have important biological functions, were examined by Western blots because of nonavailability of the IHC-compatible antibodies.…”

“…They also showed a positive association with markers of stem-like cells, including CD133 and nestin (4). In a large scale analysis of GBM by The Cancer Genome Atlas (TCGA) Network, a total of 601 genes was sequenced for detection of somatic mutations, and expression of over 12,000 genes was measured in more than 200 GBM cases to understand altered genes and pathways on the basis of copy number variations, mutation frequency analyses or differentially expressed transcripts including miRNAs (5,6). Analysis based on TCGA transcriptome data revealed that GBMs could be subtyped into four different groups, each defined by a signature of 210 transcripts (7).…”

miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways

“…Furthermore, we assessed the effects of miR-7 mimic transfection on the protein levels of all the above oncogenes and several accompanying downstream genes (23)(24)(25)(26)(27)(28)(29)(30). Western blotting showed that expression of PI3K and Raf-1 was downregulated in TJ899 cells in a dose-dependent manner after 3 days of miR-7 mimic transfection.…”

LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis

“…The Cancer Genome Atlas (TCGA) generated large-scale multi-dimensional datasets to catalogue cancer alterations. GBM is the first cancer studied by TCGA (5).…”