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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.

SUBMITTER: Lin CA

PROVIDER: S-EPMC5405724 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma.

Lin Chin-Hsing Annie CA Rhodes Christopher T CT Lin ChenWei C Phillips Joanna J JJ Berger Mitchel S MS

Cell cycle (Georgetown, Tex.) 20170222 8

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 ...[more]

PMID: 28278055

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Project description:BackgroundMolecular data of histologically classified oligodendrogliomas are available offering the possibility to stratify these human brain tumors into clinically relevant molecular subtypes.MethodsGene copy number, mutation, and expression data of 193 histologically classified oligodendrogliomas from The Cancer Genome Atlas (TCGA) were analyzed by well-established computational approaches (unsupervised clustering, statistical testing, network inference).ResultsWe applied hierarchical clustering to tumor gene copy number profiles and revealed three molecular subgroups within histologically classified oligodendrogliomas. We further screened these subgroups for molecular glioma markers (1p/19q co-deletion, IDH mutation, gain of chromosome 7 and loss of chromosome 10) and found that our subgroups largely resemble known molecular glioma subtypes. We excluded glioblastoma-like tumors (7a10d subgroup) and derived a gene expression signature distinguishing histologically classified oligodendrogliomas with concurrent 1p/19q co-deletion and IDH mutation (1p/19q subgroup) from those with predominant IDH mutation alone (IDHme subgroup). Interestingly, many signature genes were part of signaling pathways involved in the regulation of cell proliferation, differentiation, migration, and cell-cell contacts. We further learned a gene regulatory network associated with the gene expression signature revealing novel putative major regulators with functions in cytoskeleton remodeling (e.g. APBB1IP, VAV1, ARPC1B), apoptosis (CCNL2, CREB3L1), and neural development (e.g. MYTIL, SCRT1, MEF2C) potentially contributing to the manifestation of differences between both subgroups. Moreover, we revealed characteristic expression differences of several HOX and SOX transcription factors suggesting the activity of different glioma stemness programs in both subgroups.ConclusionsWe show that gene copy number profiles alone are sufficient to derive molecular subgroups of histologically classified oligodendrogliomas that are well-embedded into general glioma classification schemes. Moreover, our revealed novel putative major regulators and characteristic stemness signatures indicate that different developmental programs might be active in these subgroups, providing a basis for future studies.

Dataset Information

Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma.

Publications

Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma.

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