title: The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.
abstract: The Cancer Genome Atlas (TCGA) project has generated gene expression data that divides glioblastoma (GBM) into four transcriptional classes: proneural, neural, classical, and mesenchymal. Because transcriptional class is only partially explained by underlying genomic alterations, we hypothesize that the tumor microenvironment may also have an impact. In this study, we focused on necrosis and angiogenesis because their presence is both prognostically and biologically significant. These features were quantified in digitized histological images of TCGA GBM frozen section slides that were immediately adjacent to samples used for molecular analysis. Correlating these features with transcriptional data, we found that the mesenchymal transcriptional class was significantly enriched with GBM samples that contained a high degree of necrosis. Furthermore, among 2422 genes that correlated with the degree of necrosis in GBMs, transcription factors known to drive the mesenchymal expression class were most closely related, including C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and RUNX1. Non-mesenchymal GBMs in the TCGA data set were found to become more transcriptionally similar to the mesenchymal class with increasing levels of necrosis. In addition, high expression levels of the master mesenchymal factors C/EBP-β, C/EBP-δ, and STAT3 were associated with a poor prognosis. Strong, specific expression of C/EBP-β and C/EBP-δ by hypoxic, perinecrotic cells in GBM likely account for their tight association with necrosis and may be related to their poor prognosis.
authors.affiliation: Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Lee A D
authors.initials: LA
authors.lastname: Cooper
authors.forename: David A
authors.initials: DA
authors.lastname: Gutman
authors.forename: Candace
authors.initials: C
authors.lastname: Chisolm
authors.forename: Christina
authors.initials: C
authors.lastname: Appin
authors.forename: Jun
authors.initials: J
authors.lastname: Kong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Rong
authors.forename: Tahsin
authors.initials: T
authors.lastname: Kurc
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Joel H
authors.initials: JH
authors.lastname: Saltz
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D005909:Glioblastoma / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000473:pathology; D009154:Mutation; D009336:Necrosis; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D022782:CCAAT-Enhancer-Binding Protein-beta; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta