Modulation of transcriptional activity in brain lower grade glioma by alternative splicing.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC5957051 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe prognosis of lower-grade glioma (LGG) differs from that of other grades gliomas. Although lots of studies on the prognostic biomarkers of LGG have been reported, few have significant clinical impact. Alternative splicing (AS) events can affect cell function by splicing precursor mRNA. Therefore, a prognostic model for LGG based on AS events are important to establish.MethodsRNA sequencing, clinical, and AS event data of 510 LGG patients from the TCGA database were downloaded. Univariate Cox regression analysis was used to screen out prognostic-related AS events and LASSO regression and multivariate Cox regression were used to establish prognostic risk scores for patients in the training set (n = 340). After validation, a nomogram model was established based on the AS signature and clinical information, which was able to predict 1-, 3-, and 5-year survival rates. Finally, considering the regulatory effect of splicing factors (SFs) on AS events, an AS-SF regulatory network was analyzed.ResultsThe most common AS event was exon skipping and the least was mutually exclusive exons. All the seven AS events were related to the prognosis of LGG patients, regardless of whether they were separated or considered as a whole event (integrated AS event), and the integrated AS event had the most significant correlation. After further inclusion of clinical indicators, eight factors were screened out: age, new event, KPS, WHO grade, treatment, integrated AS signature, IDH1 and TP53 mutation status, and a nomogram model was established. The study also constructed an AS-SF regulatory network.ConclusionThe AS events and clinical factors that can predict the prognosis of LGG patients were screened, and a prognostic prediction model was established. The results of this study can play an important role in clinical work to better evaluate the prognosis of patients and impact treatment options.
| S-EPMC7774734 | biostudies-literature
Project description:Aberrant expression of RNA processing genes may drive the alterative RNA profile in lower-grade gliomas (LGGs). Thus, we aimed to further stratify LGGs based on the expression of RNA processing genes. This study included 446 LGGs from The Cancer Genome Atlas (TCGA, training set) and 171 LGGs from the Chinese Glioma Genome Atlas (CGGA, validation set). The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was conducted to develop a risk-signature. The receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used to study the prognosis value of the risk-signature. Among the tested 784 RNA processing genes, 276 were significantly correlated with the OS of LGGs. Further LASSO Cox regression identified a 19-gene risk-signature, whose risk score was also an independently prognosis factor (P<0.0001, multiplex Cox regression) in the validation dataset. The signature had better prognostic value than the traditional factors "age", "grade" and "WHO 2016 classification" for 3- and 5-year survival both two datasets (AUCs > 85%). Importantly, the risk-signature could further stratify the survival of LGGs in specific subgroups of WHO 2016 classification. Furthermore, alternative splicing events for genes such as EGFR and FGFR were found to be associated with the risk score. mRNA expression levels for genes, which participated in cell proliferation and other processes, were significantly correlated to the risk score. Our results highlight the role of RNA processing genes for further stratifying the survival of patients with LGGs and provide insight into the alternative splicing events underlying this role.
| S-EPMC6777941 | biostudies-literature
Project description:PANX2 forms large-pore channels mediating ATP release in response to physiological and pathological stimuli. Although PANX2 shows involvements in glioma genesis, the underlying mechanism remains unclear. PANX2 mRNA expression was analyzed via Oncomine and was confirmed via Gene Expression Profiling Interactive Analysis (GEPIA). The influence of PANX2 on overall survival (OS) of glioma was evaluated using LinkedOmics and further assessed through Cox regression analysis. The correlated genes with PANX2 acquired from LinkedOmics were validated through GEPIA and cBioPortal. Protein-protein interaction (PPI) of these genes was then obtained using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape with MCODE plug-in. All the PANX2-related genes underwent Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The correlation between PANX2 and cancer immune infiltrates was evaluated via Tumor Immune Estimation Resource (TIMER). A higher expression of PANX2 only revealed a better OS in brain low grade glioma (LGG). PANX2-related genes in LGG functionally enriched in neuroactive ligand-receptor interaction, synaptic vesicle cycle, and calcium signaling. The hub genes from highest module of PPI were mainly linked to chemical synaptic transmission, plasma membrane, neuropeptide, and the pathway of neuroactive ligand-receptor interaction. Besides, PANX2 expression was negatively associated with infiltrating levels of macrophage, dendritic cells, and CD4+ T cells. This study demonstrated that PANX2 likely participated in LGG pathogenesis by affecting multiple molecular pathways and immune-related processes. PANX2 was associated with LGG prognosis and might become a promising therapeutic target of LGG.
| S-EPMC10305810 | biostudies-literature
Project description:Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.
| S-EPMC7701518 | biostudies-literature
Project description:Brain low grade gliomas (LGG) often give serious clinical symptoms due to the invasion towards nervous system, affecting the life quality of patients. Collagen type I alpha 1(COL1A1) is the main component of type I collagen. Although there are many reports about abnormal expression of COL1A1 in various tumors, specific role and clinical significance of COL1A1 in LGG have not yet been elucidated. In this work, Tumor Immune Estimation Resource database was used for detecting the expression level of COL1A1 in cancer and normal tissues, and aimed to explore the relationship between COL1A1 and tumor immune infiltration. We applied Kaplan-Meier to analyze the role of COL1A1 in clinical prognosis. Univariate survival rate and multivariate Cox analysis were used to compare clinical characteristics and survival rate. The relativity between the expression of COL1A1 and the tumor microenvironment was evaluated using ESTIMATE algorithm. Finally, the relationship between expression level of COL1A1 and gene marker sets of immune cell infiltration was investigated via TIMER. According to TCGA, COL1A1 overexpression was correlated with overall survival (OS), progression free interval (PFI) and disease specific survival (DSS) of multiple tumors, especially in LGG. Multivariate analysis showed that COL1A1 expression was an independent prognostic factor for LGG. The expression of COL1A1 was positively correlated with the infiltration of CD4 + T and CD8 + T cells, neutrophils, macrophages and dendritic cells in LGG. In addition, there was a strong correlation between expression of COL1A1 and different immune marker sets in LGG. The results suggest that COL1A1 is related with tumor immune infiltration of LGG.
| S-EPMC9255759 | biostudies-literature
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage. 80 tumor samples, one normal tissue sample (brain)
2012-02-24 | E-GEOD-35158 | biostudies-arrayexpress
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage. 80 tumor samples, one normal tissue sample (brain)
| S-ECPF-GEOD-35158 | biostudies-other
Project description:BackgroundMany studies have defined a critical role for ferroptosis in cancer progression and therapy, but it is unclear how ferroptosis regulates tumor immunity or tumor microenvironment (TME).MethodsIn this study, 24 ferroptosis-regulators were assessed by nonnegative matrix factorization (NMF) consensus clustering to identify ferroptosis patterns in lower-grade gliomas (LGGs). Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method and single sample gene set enrichment analysis (ssGSEA) were used to quantify immune cell infiltrations. The PCA algorithm was used to develop the ferroptosis-related score (FRscore) to measure ferroptosis levels.ResultsTwo LGG subgroups named ferroptosis-related clusters 1 (FRC1) and 2 (FRC2), with distinct ferroptosis levels, immune infiltrations, and clinical outcomes were determined in 1,407 LGG samples. A well-designed scoring system was developed to evaluate the ferroptosis levels in LGG patients based on the FRSig gene profile and divided patients into low- and high-FRscore subgroups. Patients with low FRscores had lower ferroptosis levels and prolonged survival time and were expected to benefit from immune checkpoint blockade (ICB) therapy and showed higher sensitivity to TMZ chemotherapy. Findings also showed that the PI3K-AKT-mTOR pathway is activated by ferroptosis induction in SW1088 cells.ConclusionsThis study highlights the critical role of ferroptosis in TME formation and shaping, and quantitatively assessing ferroptosis levels in individual tumors can help to define the intratumor microenvironment and formulate precise treatment strategies for LGG patients.
| S-EPMC9113876 | biostudies-literature
Project description:The Hippo signaling pathway is a major regulator of organ growth, which controls the activity of the transcription coactivator Yorkie (Yki) in Drosophila and its homolog YAP in mammals. Both Yki and YAP proteins exist as alternatively spliced isoforms containing either one or two WW domains. The biological importance of this conserved alternative splicing event is unknown. Here, we identify the splicing factor B52 as a regulator of yki alternative splicing in Drosophila and show that B52 modulates growth in part through modulation of yki alternative splicing. Yki isoforms differ by their transcriptional activity as well as their ability to bind and bridge PPxY motifs-containing partners, and can compete in vivo. Strikingly, flies in which yki alternative splicing has been abrogated, thus expressing only Yki2 isoform, exhibit fluctuating wing asymmetry, a signal of developmental instability. Our results identify yki alternative splicing as a new level of modulation of the Hippo pathway, that is required for growth equilibration during development. This study provides the first demonstration that the process of alternative splicing contributes to developmental robustness.
| S-EPMC7849169 | biostudies-literature
Project description:Alternative splicing is central to metazoan gene regulation, but the regulatory mechanisms are incompletely understood. Here, we show that G-quadruplex (G4) motifs are enriched ~3-fold near splice junctions. The importance of G4s in RNA is emphasised by a higher enrichment for the non-template strand. RNA-seq data from mouse and human neurons reveals an enrichment of G4s at exons that were skipped following depolarisation induced by potassium chloride. We validate the formation of stable RNA G4s for three candidate splice sites by circular dichroism spectroscopy, UV-melting and fluorescence measurements. Moreover, we find that sQTLs are enriched at G4s, and a minigene experiment provides further support for their role in promoting exon inclusion. Analysis of >1,800 high-throughput experiments reveals multiple RNA binding proteins associated with G4s. Finally, exploration of G4 motifs across eleven species shows strong enrichment at splice sites in mammals and birds, suggesting an evolutionary conserved splice regulatory mechanism.
| S-EPMC9065059 | biostudies-literature