Dataset Information

The identification of mitochondrial DNA variants in glioblastoma multiforme.

ABSTRACT: Mitochondrial DNA (mtDNA) encodes key proteins of the electron transfer chain (ETC), which produces ATP through oxidative phosphorylation (OXPHOS) and is essential for cells to perform specialised functions. Tumor-initiating cells use aerobic glycolysis, a combination of glycolysis and low levels of OXPHOS, to promote rapid cell proliferation and tumor growth. Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor and mitochondria have been proposed to play a vital role in GBM tumorigenesis.Using next generation sequencing and high resolution melt analysis, we identified a large number of mtDNA variants within coding and non-coding regions of GBM cell lines and predicted their disease-causing potential through in silico modeling. The frequency of variants was greatest in the D-loop and origin of light strand replication in non-coding regions. ND6 was the most susceptible coding gene to mutation whilst ND4 had the highest frequency of mutation. Both genes encode subunits of complex I of the ETC. These variants were not detected in unaffected brain samples and many have not been previously reported. Depletion of HSR-GBM1 cells to varying degrees of their mtDNA followed by transplantation into immunedeficient mice resulted in the repopulation of the same variants during tumorigenesis. Likewise, de novo variants identified in other GBM cell lines were also incorporated. Nevertheless, ND4 and ND6 were still the most affected genes. We confirmed the presence of these variants in high grade gliomas.These novel variants contribute to GBM by rendering the ETC. partially dysfunctional. This restricts metabolism to anaerobic glycolysis and promotes cell proliferation.

SUBMITTER: Yeung KY

PROVIDER: S-EPMC3912901 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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The identification of mitochondrial DNA variants in glioblastoma multiforme.

Yeung Ka Yu KY Dickinson Adam A Donoghue Jacqueline F JF Polekhina Galina G White Stefan J SJ Grammatopoulos Dimitris K DK McKenzie Matthew M Johns Terrance G TG St John Justin C JC

Acta neuropathologica communications 20140102

<h4>Background</h4>Mitochondrial DNA (mtDNA) encodes key proteins of the electron transfer chain (ETC), which produces ATP through oxidative phosphorylation (OXPHOS) and is essential for cells to perform specialised functions. Tumor-initiating cells use aerobic glycolysis, a combination of glycolysis and low levels of OXPHOS, to promote rapid cell proliferation and tumor growth. Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor and mitochondria have been proposed to play a v ...[more]

PMID: 24383468

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Project description:BACKGROUND:Alternative exon usage (AEU) is an important component of gene regulation. Exon expression platforms allow the detection of associations between AEU and phenotypes such as cancer. Numerous studies have identified associations between gene expression and the brain cancer glioblastoma multiforme (GBM). The few consistent gene expression biomarkers of GBM that have been reported may be due to the limited consideration of AEU and the analytical approaches used. The objectives of this study were to develop a model that accounts for the variations in expression present between the exons within a gene and to identify AEU biomarkers of GBM survival. METHODS:The expression of exons corresponding to 25,403 genes was related to the survival of 250 individuals diagnosed with GBM in a training data set. Genes exhibiting AEU in the training data set were confirmed in an independent validation data set of 78 patients. A hierarchical mixed model that allows the consideration of covariation between exons within a gene and of the effect of the epidemiological characteristics of the patients was developed to identify associations between exon expression and patient survival. This general model describes all three possible scenarios: multi-exon genes with and without AEU, and single-exon genes. RESULTS:AEU associated with GBM survival was identified on 2477 genes (P-value < 5.0E-04 or FDR-adjusted P-value < 0.05). G-protein coupled receptor 98 (Gpr98) and epidermal growth factor (Egf) were among the genes exhibiting AEU with 30 and 9 exons associated with GBM survival, respectively. Pathways enriched among the AEU genes included focal adhesion, ECM-receptor interaction, ABC transporters and pathways in cancer. In addition, 24 multi-exon genes without AEU and 8 single-exon genes were associated with GBM survival (FDR-adjusted P-value < 0.05). CONCLUSIONS:The inferred patterns of AEU were consistent with in silico AS models. The hierarchical model used offered a flexible and simple way to interpret and identify associations between survival that accommodates multi-exon genes with or without AEU and single exon genes. Our results indicate that differential expression of AEU could be used as biomarker for GBM and potentially other cancers.

Project description:BackgroundGlioblastoma multiforme (GBM) is the most malignant type of glioma. GBM tumors grow rapidly, have a high degree of malignancy, and are characterized by a fast disease progression. Unfortunately, there is a lack of effective treatments. An effective strategy for the treatment of GBM would be to identify key biomarkers correlating with the occurrence and progression of GBM and developing these biomarkers into therapeutic targets.Method and resultsIn this study, using integrated bioinformatics analysis, we identified differentially expressed genes (DEGs), including 130 genes that were upregulated in GBM compared to normal brain tissue, and 128 genes that were downregulated in GBM. Based on Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis, these genes were associated with regulation of tumor cell adhesion, differentiation, morphology in GBM and were mainly enriched in Complement and coagulation cascades pathway. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to construct a Protein-Protein Interaction network. Ten hub genes were identified, including FN1, CD44, MYC, CDK1, SERPINE1, COL3A1, COL1A2, LOX, POSTN and EZH2, all of which were significantly upregulated in GBM, these results were confirmed by oncomine database exploration. Alteration analysis of hub genes found that patients with alteration in at least one of the hub genes showed shorter median survival times (p = 0.013) and shorter median disease-free survival times (p = 2.488E-3) than patients without alterations in any of the hub genes. Multiple tests for survival analysis showed that among individual hub genes only expression of LOX was correlated with patient survival (P < 0.05).GDS4467 data set was used to analyze the expression of LOX in gliomas with different degrees of malignancy, and it was found that the expression level of LOX was positively correlated with the malignant degree of gliomas.By analyzing GDS 4535 data set showed that the expression level of LOX was positively correlated with the differentiation degree of GBM cells CONCLUSION: This research suggests that FN1, CD44, MYC, CDK1, SERPINE1, COL3A1, COL1A2, LOX, POSTN and EZH2 are key genes in GBM. However, only LOX is correlated with patient survival and promotes glioblastoma cell differentiation and tumor recurrence. LOX may be a candidate prognostic biomarker and potential therapeutic target for GBM.

Project description:PurposeHOXD10 is a tumor modulator that can either be a tumor-suppressor or a tumor-promoting gene. However, the role of HOXD10 in glioblastoma multiforme (GBM) remains unclear.MethodsImmunohistochemistry (IHC) was applied to detect protein expression of HOXD10 in GBM and normal brain tissue patients. Clinicopathological characteristics with GBM were recorded, and a Kaplan-Meier curve was plotted. Additionally, the mRNA expression of HOXD10 and its effect on prognosis were analyzed using the online tool GEPIA and the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO) databases. Based on the mRNA expression of HOXD10, GBM patients from TCGA database were divided into low- and high-HOXD10 expression groups to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and construct a lncRNA-miRNA-mRNA network and a protein-protein interaction (PPI) network.ResultsThe mRNA expression of HOXD10 was up-regulated in GBM according to GEPIA, while the protein expression of HOXD10 in GBM was down-regulated according to IHC analysis of samples from patients collected from our hospital. Correlation analysis showed that HOXD10 expression was significantly related to IDH1 status. Univariate analysis revealed that low HOXD10 expression, complete surgical resection, postoperative radiotherapy, postoperative temozolomide chemotherapy and IDH1 mutation were all beneficial prognostic factors. Further multivariate analysis revealed that only complete surgical resection and postoperative radiotherapy were independent prognostic factors. GO and KEGG enrichment analyses indicated that HOXD10 expression is mainly involved in cytokine-cytokine receptor interactions. In the ceRNA network, 89 nodes, containing 45 mRNAs, 39 miRNAs and five lncRNAs associated with prognosis were involved. The PPI network revealed a tight interaction between HOXD10 and HOXD8, HOXD9, HOXD11, HOXD13 and HOXB3.ConclusionBased on our experimental data, although HOXD10 expression is low in GBM compared with normal brain tissue, GBM patients with high HOXD10 expression have a worse prognosis. HOXD10 may play different or even opposite roles in different stages of GBM occurrence and development. For patients with GBM, HOXD10 may be a valid predictor of prognosis.

Dataset Information

The identification of mitochondrial DNA variants in glioblastoma multiforme.

Publications

The identification of mitochondrial DNA variants in glioblastoma multiforme.

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