title: Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma.
abstract: Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM. In the absence of IDH mutation, several genes associated with metabolism are differentially expressed in these subtypes of primary GBM, implicating metabolic reprogramming occurs in tumor microenvironment. Furthermore, histone lysine methyltransferase EZH2 was upregulated while histone lysine demethylases KDM2 and KDM4 were downregulated in both group I and II primary GBM. Lastly, we identified 9 common genes across large data sets of gene expression profiles among MRI-classified group I/II GBM, a large cohort of GBM subtypes from TCGA, and glioma stem cells by unsupervised clustering comparison. These commonly upregulated genes have known functions in cell cycle, centromere assembly, chromosome segregation, and mitotic progression. Our findings highlight altered expression of genes important in chromosome integrity across all GBM, suggesting a common mechanism of disrupted fidelity of chromosome structure in GBM.
authors.affiliation: a Department of Biology , University of Texas at San Antonio , San Antonio , TX , USA.|b Neuroscience Institute , University of Texas at San Antonio , San Antonio , TX , USA.
authors.forename: Chin-Hsing Annie
authors.initials: CA
authors.lastname: Lin
authors.affiliation: a Department of Biology , University of Texas at San Antonio , San Antonio , TX , USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Rhodes
authors.affiliation: c Clinical Research Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors.forename: ChenWei
authors.initials: C
authors.lastname: Lin
authors.affiliation: d Department of Neurological Surgery , University of California , San Francisco , CA , USA.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: d Department of Neurological Surgery , University of California , San Francisco , CA , USA.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
mesh_terms: D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D020547:Lateral Ventricles / Q000473:pathology*; D008239:Lysine / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008745:Methylation; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D017423:Sequence Analysis, RNA
chemical_list: D006657:Histones; D007521:Isocitrate Dehydrogenase; D008239:Lysine
keywords: Enhancer of zeste (Human- Gene: EZH2; Glioblastoma (GBM); Glioma stem cells (GSC); Histone lysine demethylase (KDM); Neural Stem Progenitor Cells (NSPCs); Protein: EZH2); subventricular zone (SVZ); tri-methylation at histone 3 lysine 27 (H3K27me3)