Genetic and Lineage Classification of Glioma-Initiating Cells Identifies a Clinically Relevant Glioblastoma Model.
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ABSTRACT:
SUBMITTER: Saito N
PROVIDER: S-EPMC6826962 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Glioblastoma is the most lethal primary brain tumor in adults. Aberrant signal transduction pathways, associated with the progression of glioblastoma, have been identified recently and may offer a potential gene therapy strategy. Methods and Findings: We first used the sample level enrichment analysis to transfer gene expression profile of TCGA dataset into pathway enrichment z-score matrix. Then, we classified glioblastoma into five subtypes (Cluster A to Cluster E) by the consensus clustering and silhouette analysis. Principle component analysis showed the five subtype could be separated by first three principle components. Integrative omics data showed that mesenchymal subtype was rich in Cluster A, neural subtype was centered in Cluster D and proneural subtype was gathered in Cluster E, while Cluster E showed a high percentage of G-CIMP subtype. Additionally, according to analyze the overall survival and progression free survival of each subtype by Kaplan-Merie analysis and Cox hazard proportion model, we identified Cluster D and Cluster E received a better prognosis. Conclusions: We report a clinically relevant classification of glioblastoma based on sample level KEGG pathway enrichment profile and this novel classification system provided new insights into the heterogeneity of glioblastoma, and may be used as an important clinical tool to predict the prognosis.
| S-EPMC5039391 | biostudies-literature
Project description:Glioblastoma (GBM) is maintained by a small subpopulation of tumor-initiating cells (TICs). The arduous assessment of TIC frequencies challenges the prognostic role of TICs in predicting the clinical outcome in GBM patients. We estimated the TIC frequency in human GBM injecting intracerebrally in mice dissociated cells without any passage in culture.All GBMs contained rare TICsand were tumorigenic in vivo but only 54% of them grew in vitro as neurospheres. We demonstrated that neurosphere formation in vitro did not foretell tumorigenic ability in vivo and frequencies calculated in vitro overestimated the TIC content.Our findings assert the pathological significance of GBM TICs. TIC number correlated positively with tumor incidence and inversely with survival of tumor-bearing mice. Stratification of GBM patients according to TIC content revealed that patients with low TIC frequency experienced a trend towards a longer progression free survival. The expression of either putative stem-cell markers or markers associated with different GBM molecular subtypes did not associate with either TIC content or neurosphere formation underlying the limitations of TIC identification based on the expression of some putative stem cell-markers.
| S-EPMC5342095 | biostudies-literature
Project description:The major part of the genome that was previously called junk DNA has been shown to be dynamically transcribed to produce non-coding RNAs. Among them, the long non-coding RNAs (lncRNA) play diverse roles in the cellular context and are therefore involved in various diseases like cancer. LncRNA transcript profiling of glioblastoma (n = 19) and control brain samples (n = 9) identified 2,774 and 5,016 lncRNAs to be upregulated and downregulated in GBMs respectively. Correlation analysis of differentially regulated lncRNAs with mRNA and lncRNA identified several lncRNAs that may potentially regulate many tumor relevant mRNAs and lncRNAs both at nearby locations (cis) and far locations (trans). Integration of our data set with TCGA GBM RNA-Seq data (n = 172) revealed many lncRNAs as a host as well as decoy for many tumor regulated miRNAs. The expression pattern of seven lncRNAs- HOXD-AS2, RP4-792G4.2, CRNDE, ANRIL, RP11-389G6.3, RP11-325122.2 and AC123886.2 was validated by TCGA RNA-Seq data and RT-qPCR. Silencing ANRIL, a GBM upregulated lncRNA, inhibited glioma cell proliferation and colony growth. Cox regression analysis identified several prognostic lncRNAs. An lncRNA risk score derived from five lnRNAs-RP6-99M1.2, SOX21-AS1, CTD-2127H9.1, RP11-375B1.3 and RP3-449M8.9 predicted survival independent of all other markers. Multivariate cox regression analysis involving G-CIMP, IDH1 mutation, MGMT promoter methylation identified lncRNA risk score to be an independent poor predictor of GBM survival. The lncRNA risk score also stratified GBM patients into low and high risk with significant survival difference. Thus our study demonstrates the importance of lncRNA in GBM pathology and underscores the potential possibility of targeting lncRNA for GBM therapy.
| S-EPMC6049862 | biostudies-other
Project description:Objective: The clinical presentation and course of Crohn’s disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterize the cellular processes associated with disease phenotypes. Design: We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult CD and control patients. To support the generality of our findings, we analyzed previously published expression data from a large cohort of treatment-naïve pediatric CD and control ileum. Results: We found that adult CD patients clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Further, gene expression from the ilea of the treatment-naïve pediatric CD patient cohort could be similarly subdivided into colon- and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behavior, including rectal and perianal disease and need for colectomy. Conclusion: Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.
2016-12-11 | GSE85499 | GEO
Project description:The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.
| S-EPMC2818769 | biostudies-literature
Project description:BackgroundThe metabolic preference of malignant glioma for glycolysis as an energy source is a potential therapeutic target. As a result of the cellular heterogeneity of these tumors, however, the relation between glycolytic preference, tumor formation, and tumor cell clonogenicity has remained unknown. To address this issue, we analyzed the metabolic profiles of isogenic glioma-initiating cells (GICs) in a mouse model.MethodsGICs were established by overexpression of H-Ras(V12) in Ink4a/Arf-null neural stem cells. Subpopulations of these cells were obtained by single-cell cloning, and clones differing in extracellular acidification potential were assessed for metabolic characteristics. Tumors formed after intracranial implantation of these clones in mice were examined for pathological features of glioma and expression of glycolytic enzymes.ResultsMalignant transformation of neural stem cells resulted in a shift in metabolism characterized by an increase in lactic acid production. However, isogenic clonal populations of GICs manifested pronounced differences in glucose and oxygen consumption, lactate production, and nucleoside levels. These differences were paralleled by differential expression of glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2, with this differential expression also being evident in tumors formed by these clones in vivo.ConclusionsThe metabolic characteristics of glioma cells appear early during malignant transformation and persist until the late stages of tumor formation. Even isogenic clones may be heterogeneous in terms of metabolic features, however, suggesting that a more detailed understanding of the metabolic profile of glioma is imperative for effective therapeutic targeting.
| S-EPMC4096179 | biostudies-literature
Project description:The exact biological mechanism governing the radioresistant phenotype of prostate tumours at a high risk of recurrence despite the delivery of advanced radiotherapy protocols remains unclear. This study analysed the protein expression profiles of a previously generated isogenic 22Rv1 prostate cancer model of radioresistance using DigiWest multiplex protein profiling for a selection of 90 signalling proteins. Comparative analysis of the profiles identified a substantial change in the expression of 43 proteins. Differential PARP-1, AR, p53, Notch-3 and YB-1 protein levels were independently validated using Western Blotting. Pharmacological targeting of these proteins was associated with a mild but significant radiosensitisation effect at 4Gy. This study supports the clinical relevance of isogenic in vitro models of radioresistance and clarifies the molecular radiation response of prostate cancer cells.
| S-EPMC6874565 | biostudies-literature
Project description:The outcome of patients with anaplastic gliomas varies considerably depending on histology and single molecular markers such as codeletion of 1p/19q and mutations of the isocitrate dehydrogenase (IDH) gene. Whether a molecularly-based classification of anaplastic gliomas based on large scale genomic or epigenomic analyses is superior to histopathology, may reflect distinct biological subtypes, predict outcome and guide therapy decisions had yet to be determined. Epigenome-wide DNA methylation analysis, which also allows for the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering demonstrated two main groups based on IDH mutation status: CpG island methylator phenotype (CIMP) positive (77.5%) or negative (22.5%). CIMP+ (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q, but not based on histopathology. CIMP- (IDH wild type) tumors on the other hand showed hallmark copy-number alterations of glioblastomas. These tumors clustered together with CIMP- glioblastomas without forming separate groups based on WHO grade. There was no Tumor classification based on CIMP and 1p/19q status was significantly associated with survival allowing a better prediction of outcome than the current histopathological classification alone: Patients with CIMP+ tumors with 1p/19q codeletion had the best prognosis, followed by patients with CIMP+ but intact 1p/19q status. Patients with CIMP- anaplastic gliomas had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped into three molecular subtypes with clear association to underlying biology and clinical outcome based on IDH and 1p/19q status. The data do not provide a molecular basis for the diagnosis of anaplastic oligoastrocytoma. We investigated a subset of 228 anaplastic gliomas using the Illumina 450k methylation array.
2014-06-06 | E-GEOD-58218 | biostudies-arrayexpress
Project description:Colorectal cancer (CRC) is a heterogeneous disease classified into four consensus molecular subtype (CMSs) with distinct biological and clinical features. This study aims to understand the value of patient-derived xenografts (PDXs) in relation to these CMSs. A total of 42 primary tumors, recurrences and metastases were used to develop PDXs. Detailed genetic analyses were performed on PDXs and corresponding patient tumors to determine relationship and PDX heterogeneity. Out of 42 tumors 22 (52%) showed successfully PDX engraftment, which was biased towards metastases and CMS1 and CMS4 tumors. Importantly, gene expression analysis revealed a clinical relevant association between an engraftment gene signature and prognosis for stage II patients. Moreover, this gene signature revealed an association between Src pathway activation and positive engraftment. Src pathway activity co-aligned with CMS4 and the levels of fibronectin in tumors and was confirmed by pSrc immunohistochemistry. From this analysis we further deduced that decreased cell cycle activity is a prognostic factor for successful engraftment and related to patient prognosis. However, this is not a general phenomenon, but subtype specific as decreased cell cycle activity was highly prognostic for recurrence-free survival within CMS2 but not in CMS1 and CMS4, while it showed an inverse correlation in CMS3. These data illustrate that CRC PDX establishment is biased toward CMS1 and CMS4, which impacts translation of results derived from pre-clinical studies using PDXs. Moreover, our analysis reveals subtype-specific features, pSrc in CMS4 and low Ki67 in CMS2, which provide novel avenues for therapy and diagnosis.
2018-10-16 | GSE103340 | GEO
Project description:ObjectiveThe clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.DesignWe examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult patients with CD and control patients. To support the generality of our findings, we analysed previously published expression data from a large cohort of treatment-naïve paediatric CD and control ileum.ResultsWe found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression-one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatment-naïve cohort of paediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behaviour, including rectal disease and need for colectomy.ConclusionsOur results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.
| S-EPMC5426990 | biostudies-literature