Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.
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ABSTRACT:
SUBMITTER: Kinker GS
PROVIDER: S-EPMC4823696 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pleomorphic adenoma gene like-2 (PLAGL2) has been implicated in the development and progression of diverse malignancies, including glioblastoma. An increasing number of studies have reported that dysregulated expression of PLAGL2 is a common phenomenon in different malignancies. However, the mechanism and biological functions of PLAGL2 in patients with high-grade glioma (HGG) remain unclear. In addition, the expression and clinical significance of PLAGL2 in HGG have not yet been reported. Herein, we investigated the expression patterns and prognostic values of PLAGL2 in patients with HGG by using various databases, including Tumor Immune Estimation Resource 2.0 (TIMER2.0), GENT2, ONCOMINE, GEPIA, Human Protein Atlas, and Gene Expression Omnibus datasets. In the present study, we analyzed the relationship between PLAGL2 mRNA expression and clinical parameters in 184 HGG cases and found that PLAGL2 presented positively high expression and was relevant to poor prognosis. Immunohistochemistry analysis confirmed the overexpression of PLAGL2 protein, which is mainly expressed in the nucleus of glioma. Additionally, a high level of expression of the PLAGL2 gene was associated with lower survival in progression-free survival and overall survival in GBM patients. The correlation analysis between PLAGL2 and immune infiltration related to the abundance of B cells, CD8+ T cells, CD4+ T cells, macrophages, DCs, and neutrophils was also performed using TIMER2.0. GSEA results showed that high PLAGL2 expression was associated with cell migration, proliferation, actin cytoskeletal, and angiogenesis. To sum up, our findings indicated that PLAGL2 could serve as an independent prognostic biomarker and might be a potential therapeutic target for HGG, which should be further investigated.
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Project description:BackgroundThe IGFBP family of insulin-like growth factor binding proteins has important biological functions in the organism. However, the role of the IGFBP family in low-grade glioma (LGG) has not been fully explored.MethodsWe validated the clinical value of the IGFBP family using RNA-seq and clinical data of LGG in the TCGA and constructed an IGFBPScore using LASSO-regression analysis for prognosis prediction, subtype determination, and treatment sensitivity determination. Subsequently, we explored the role of the IGFBP family in the development of LGG using PanCanAtlas data.ResultsOur results suggest that most IGFBP family members were aberrantly expressed and were strongly associated with poor prognosis in LGG. By constructing an IGFBPScore representing the IGFBP family, we found that tumor samples with a high IGFBPScore had a glioblastoma-like mutation pattern characterized by IDH1wt, EGFRmut, PTENmut, and NF1mut with hypo-methylation and glioma stem cell (GSC) diversity. In contrast, the low IGFBPScore group was characterized by IDH1mut accompanied by TP53mut, CICmut, and ATRXmut, and had hyper-methylation status as well as the GSC restriction. Additionally, the high-IGFBPScore group had a high inflammation phenotype with increased immune antigenicity and increased infiltration of immune molecules and cells, as well as a high extracellular matrix phenotype and enhanced multiple metabolic pathways compared with the immune-quiet phenotype of the low-IGFBPScore group, which was strongly associated with poor prognosis.ConclusionOur study provides a summary analysis and a theoretical basis for the biological role and clinical value of the IGFBP family in LGG, providing an important therapeutic target for LGG.
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Project description:AimLow grade glioma (LGG) is a lethal brain cancer with relatively poor prognosis in young adults. Thus, this study was performed to develop novel molecular biomarkers to effectively predict the prognosis of LGG patients and finally guide treatment decisions.Methodssurvival-related genes were determined by Kaplan-Meier survival analysis and multivariate Cox regression analysis using the expression and clinical data of 506 LGG patients from The Cancer Genome Atlas (TCGA) database and independently validated in a Chinese Glioma Genome Atlas (CGGA) dataset. A prognostic risk score was established based on a linear combination of 10 gene expression levels using the regression coefficients of the multivariate Cox regression models. GSEA was performed to analyze the altered signaling pathways between the high and low risk groups stratified by median risk score.ResultsWe identified a total of 1489 genes significantly correlated with patients' prognosis in LGG. The top 5 protective genes were DISP2, CKMT1B, AQP7, GPR162 and CHGB, the top 5 risk genes were SP1, EYA3, ZSCAN20, ITPRIPL1 and ZNF217 in LGG. The risk score was predictive of poor overall survival and relapse-free survival in LGG patients. Pathways of small cell lung cancer, pathways in cancer, chronic myeloid leukemia, colorectal cancer were the top 4 most enriched pathways in the high risk group. SP1, EYA3, ZSCAN20, ITPRIPL1, ZNF217 and GPR162 were significantly up-regulated, while DISP2, CKMT1B, AQP7 were down-regulated in 523 LGG tissues as compared to 1141 normal brain controls.ConclusionsThe 10-gene signature may become novel prognostic and diagnostic biomarkers to considerably improve the prognostic prediction in LGG.
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Project description:BackgroundLUZP2 is a protein limitedly expressed in the brain and spinal cord, while there are few studies on it in brain tumors. Low-grade glioma (LGG) is one of the most common brain tumors. However, the biological behavior of LGG is not very clear at present. This study was aimed at exploring the role of LUZP2 in LGG.MethodsBy data mining in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), the expression, clinical characteristics, and potential regulatory mechanism of LUZP2 in LGG were assessed. The regulatory miRNAs of LUZP2 were predicted using miRDB, TargetScan, and miRTarBase. Meanwhile, the potential biological function of coexpressed genes was investigated by GO and KEGG analyses.ResultsLUZP2 expression was downregulated with the increase of tumor grade (p < 0.05). Low LUZP2 expression independently predicted poor OS in LGG in TCGA cohort and the CGGA part B and part C cohorts (all p < 0.001). Additionally, LUZP2 was targeted by miR-142-5p according to 2 prediction databases and 1 validated database, which was negatively related to LUZP2 mRNA expression (p < 0.001). Kaplan-Meier analyses demonstrated that low miR-142-5p expression was significantly associated with poor OS (p < 0.001). Furthermore, coexpression genes of LUZP2 were significantly involved in nervous system development and metabolic pathways.ConclusionsLUZP2 may be crucial for nervous system extracellular matrix development and serve as an important clinical biomarker for LGG patients. miR-142-5p upregulation could be the upstream regulator that contributed to LUZP2 downregulation.
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Project description:Gliomas make up ~80% of malignant brain tumors in adults and are responsible for the majority of deaths from primary brain tumors. The glioma tumor microenvironment (TME) is a dynamic, heterogeneous mixture of extracellular matrix and malignant and non-malignant cells. Several ongoing clinical trials are evaluating the efficacy of therapies that target non-malignant cells, particularly immune cells. Consequently, a better understanding of the TME in glioma is pertinent. We utilized several gene expression datasets to evaluate the relationship between immune-related genes (IRGs) and patient prognosis. We generated microglia signatures using single-cell RNAseq data from human and mouse glioma cells to infer microglia abundance. Lastly, we built a LASSO Cox regression model that predicts patient survival. We found that 428 IRGs were negatively associated with survival in glioma patients. Overall survival was significantly lower in those with a high level of microglia infiltration. In addition, we also found that microglia abundance was significantly associated with several common genomic aberrations, including IDH2 and TP53 mutations. Furthermore, we found that patients with high risk scores had significantly worse overall survival than those with low risk scores in several independent datasets. Altogether, we characterized immune features predictive of overall survival in glioma and found that microglia abundance is negatively associated with survival. We developed a 23-gene risk score that can significantly stratify patients into low- and high-risk categories.
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Project description:BackgroundTyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG).MethodsThe differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database.ResultsSixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG.ConclusionTYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.
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Project description:ObjectiveMitochondrial genome maintenance exonuclease 1 (MGME1) is associated with DNA depletion, deletion, duplication, and rearrangement. However, the function of MGME1 in tumors, especially lower-grade gliomas (LGGs), has not been established.MethodsPan-cancer analysis was used to define the expression patterns and prognostic value of MGME1 in various cancers. Subsequently, we systematically determined the associations between MGME1 expression and clinicopathological characteristics, prognosis, biological functions, immune characteristics, genomic mutations, and therapeutic responses of LGGs based on their expression patterns. The expression level and specific functions of MGME1 in LGGs was detected by conducting in vitro experiments.ResultsAbnormally enhanced and high MGME1 expressions were associated with poor prognoses of various tumors, including LGG. Multivariate and univariate Cox regression analyses manifested that MGME1 expression was an independent prognostic biomarker for LGG. The immune-related signatures, infiltration of immune cells, immune checkpoint genes (ICPGs), copy number alteration (CNA), tumor mutation burden (TMB), and treatment responses of LGG patients were associated with the expression of MGME1. The in vitro experiments affirmed that MGME1 was elevated and tightly connected with the cell proliferation and cell cycle in LGG.ConclusionsMGME1 is an independent prognostic biomarker and closely related to the cell proliferation in LGG.
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Project description:ObjectiveMago-nashi homolog (MAGOH) has been shown to play a pivotal part in various tumors. However, its specific contribution in lower-grade glioma (LGG) is still unknown.MethodsPan-cancer analysis was implemented to inspect the expression characteristics and prognostic significance of MAGOH in multiple tumors. The associations between MAGOH expression patterns and the pathological features of LGG were analyzed, as were the connections between MAGOH expression and the clinical traits, prognosis, biological activities, immune features, genomic variations, and responses to treatment in LGG. Additionally, in vitro studies were performed to detect the expression levels and biomedical functions of MAGOH in LGG.ResultsAbnormally increased levels of MAGOH expression were connected with adverse prognosis in patients with several types of tumors, including LGG. Importantly, we found that levels of MAGOH expression were independent prognostic biomarker of patients with LGG. Increased MAGOH expression was also highly associated with several immune-related markers, immune cell infiltration, immune checkpoint genes (ICPGs), gene mutations, and responses to chemotherapy in patients with LGG. In vitro studies ascertained that abnormally increased MAGOH was essential for cell proliferation in LGG.ConclusionMAGOH is a valid predictive biomarker in LGG and may become a novel therapeutic target in these patients.
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Project description:Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) functions as an oncogene in several types of tumor. Nevertheless, the potential function of CNIH4 in lower-grade glioma (LGG) remains unclear. Pan-cancer analysis was implemented to comprehensively explore CNIH4 expression patterns and prognostic value in multiple cancers. Further, a systematic investigation of correlations between CNIH4 expression and clinical features, prognosis, biological functions, immune properties, genomic mutations, and treatment response was conducted, based on LGG expression patterns. CNIH4 expression levels and specific roles in LGG were also evaluated using in vitro experiments. Aberrant CNIH4 overexpression was detected in various tumors, and higher CNIH4 expression was linked with inferior prognosis, including in patients with LGG. Univariate and multivariate Cox regression analysis indicated that CNIH4 expression was an independent prognostic biomarker in patients with LGG. Our data also revealed that CNIH4 expression was strongly related to immune-associated signatures, immune cell infiltration, immune checkpoint genes, copy number alteration burden, tumor mutation burden, and treatment response in patients with LGG. In vitro experiments confirmed that CNIH4 was unusually elevated and crucial for cell proliferation, migration, invasion and cell cycle regulation in LGG. Together, our data validate CNIH4 may be an independent prognostic biomarker that could serve as a novel therapeutic target for improvement of prognosis in patients with LGG.
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Project description:Purpose: Glioma is the most common malignant brain tumor. The molecular mechanisms underlying its malignancy are not fully understood. LAMC1, which encodes extracellular matrix protein laminin ?1, has been implicated in some malignant tumors but has not been systematically evaluated in glioma. The aim of this study was to evaluate the expression of LAMC1 and its clinical significance. Patients and methods: LAMC1 protein expression in 52 fresh-frozen specimens of different pathological grade gliomas and 5 normal brain tissues was detected by Western blotting. Immunohistochemistry was used to detect LAMC1 protein expression in another set of 76 glioma tissues and 8 normal brain tissues. The associations between clinicopathological factors and LAMC1 expression were analyzed. A log-rank test and a multivariate Cox proportional hazards model were used to determine the relationship between LAMC1 expression and patient prognosis. The expression of LAMC1 at the mRNA level was analyzed in the TCGA database. Results: LAMC1 was highly expressed in high-grade glioma tissues, with moderate expression in low-grade gliomas, and weak or no expression in normal brain tissues, as detected by Western blotting and immunohistochemistry. A chi-square test indicated that LAMC1 expression was associated with pathological grade but not with other clinicopathological factors, such as age, sex, and tumor size. LAMC1 expression at the mRNA level was upregulated in high-grade gliomas compared with low-grade gliomas and normal brain tissue in the TCGA database. The Kaplan-Meier plot and log-rank test in our patient series showed that high LAMC1 expression was significantly associated with shorter survival, which was consistent with the TCGA database analysis. A multivariate Cox proportional hazards model revealed that LAMC1 expression, WHO grade, and surgery procedure were significantly correlated with overall survival and progression-free survival. Conclusion: These results demonstrated that LAMC1 may play an important role in glioma progression and may be used in the diagnosis, prognosis, and targeted therapy of glioma patients.
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