Coexpression Network Analysis Identifies Transcriptional Modules Related to Proastrocytic Differentiation and Sprouty Signaling in Glioma

Abstract

Gliomas are primary brain tumors with high mortality and heterogeneous biology that is insufficiently understood. In this study, we performed a systematic analysis of the intrinsic organization of complex glioma transcriptome to gain deeper knowledge of the tumor biology. Gene coexpression relationships were explored in 790 glioma samples from 5 published patient cohorts treated at different institutions. We identified 20 coexpression modules that were common to all the data sets and associated with proliferation, angiogenesis, hypoxia, immune response, genomic alterations, cell differentiation phenotypes, and other features inherent to glial tumors. A collection of high-quality signatures for the respective processes was obtained using cross-data set summarization of the modules' gene composition. Individual modules were found to be organized into higher order coexpression groups, the two largest of them associated with glioblastoma and oligodendroglioma, respectively. We identified a novel prognostic gene expression signature (185 genes) linked to a proastrocytic pattern of tumor cell differentiation. This "proastrocytic" signature was associated with long survival and defined a subgroup of the previously established "proneural" class of gliomas. A strong negative correlation between proastrocytic and proneural markers across differentiated tumors underscored the distinction between these subtypes of glioma. Interestingly, one further novel signature in glioma was identified that was associated with EGFR (epidermal growth factor receptor) gene amplification and suggested that EGF signaling in glioma may be a subject to regulation by Sprouty family proteins. In summary, this integrated analysis of the glioma transcriptome provided several novel insights into molecular heterogeneity and pathogenesis of glial tumors.

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

“…Unfortunately, the underlying molecular mechanisms of unlimited proliferation and progressive local invasion remain obscure. Previous work has demonstrated that GBM frequently harbors mutations that activate EGFR and launch downstream signaling pathways, including the PI3K/ATK and Ras/Raf/MEK/ERK pathways (6,8,32). However, EGFR-Ras or PI3K mutations alone are not sufficient to transform glial cells; instead, multiple mutations that coactivate the EGFR-Ras and PI3K/Akt pathways are necessary to induce glioma (33).…”

“…Among these, EGFR plays a vital role in various aspects of malignancy, particularly in tumor cell proliferation, survival and metastasis (4,5). Glioma-associated EGFR mutant forms show constitutive kinase activity that chronically stimulates Ras signaling to drive cell cycle progression and also activates the PI3K/AKT pathway to promote cellular proliferation and migration (6)(7)(8).…”

Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas

“…14 Ivliev et al also identified transcriptional modules related to proastrocytic differentiation and sprout signaling in gliomas. 16 In our study, among the 23 coexpression modules, we identified one that was strongly associated with tumorigenesis and could be considered an oncogenic module. This module contains 356 genes and is enriched in glycoprotein/membrane/blood vessel development and cell migration.…”

“…2,6,45 The WGCNA approach has been widely used to identify potential oncogenic coexpression modules and predict the molecular targets and prognosis markers. 14,16,38,55,58 For instance, Horvath et al have successfully identified the gene ASPM as a molecular target for glioblastoma, another primary brain tumor. 14 Ivliev et al also identified transcriptional modules related to proastrocytic differentiation and sprout signaling in gliomas.…”

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila))

“…Note Analysis of a glioma dataset containing expression data from 276 tumor samples revealed that SPROUTY (SPRY1, SPRY2, and SPRY4) genes are coordinately upregulated in EGFR amplified gliomas (Ivliev et al, 2010). The role and significance of SPRY1 in glioma has not been functionally addressed.…”