scholarly journals Integrated Analysis Reveals Prognostic Value and Immune Correlates of CD86 Expression in Lower Grade Glioma

2021 ◽  
Vol 11 ◽  
Author(s):  
Huaide Qiu ◽  
Wei Tian ◽  
Yikang He ◽  
Jiahui Li ◽  
Chuan He ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Prognostic Factor ◽  
Prognostic Value ◽  
Integrated Analysis ◽  
Lower Grade ◽  
Qrt Pcr ◽  
Lower Grade Glioma ◽  
Pan Cancer ◽  
Genome Atlas

BackgroundCD86 has great potential to be a new target of immunotherapy by regulating cancer immune response. However, it remains unclear whether CD86 is a friend or foe in lower-grade glioma (LGG).MethodsThe prognostic value of CD86 expression in pan-cancer was analyzed using Cox regression and Kaplan-Meier analysis with data from the cancer genome atlas (TCGA). Cancer types where CD86 showed prognostic value in overall survival and disease-specific survival were identified for further analyses. The Chinese Glioma Genome Atlas (CGGA) dataset were utilized for external validation. Quantitative real-time PCR (qRT-PCR), Western blot (WB), and Immunohistochemistry (IHC) were conducted for further validation using surgical samples from Jiangsu Province hospital. The correlations between CD86 expression and tumor immunity were analyzed using the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, Tumor IMmune Estimation Resource (TIMER) database, and expressions of immune checkpoint molecules. Gene Set Enrichment Analysis (GSEA) was performed using clusterprofiler r package to reveal potential pathways.ResultsPan-cancer survival analysis established CD86 expression as an unfavorable prognostic factor in tumor progression and survival for LGG. CD86 expression between Grade-II and Grade-III LGG was validated using qRT-PCR and WB. Additionally, CD86 expression in LGG with unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter was significantly higher than those with methylated MGMT (P<0.05), while in LGG with codeletion of 1p/19q it was significantly downregulated as opposed to those with non-codeletion (P<2.2*10-16). IHC staining validated that CD86 expression was correlated with MGMT status and X1p/19q subtypes, which was independent of tumor grade. Multivariate regression validated that CD86 expression acts as an unfavorable prognostic factor independent of clinicopathological factors in overall survival of LGG patients. Analysis of tumor immunity and GSEA revealed pivotal role of CD86 in immune response for LGG.ConclusionsIntegrated analysis shows that CD86 is an unfavorable prognostic biomarker in LGG patients. Targeting CD86 may become a novel approach for immunotherapy of LGG.

scholarly journals Prognostic Value of Immune-Related lncRNA SBF2-AS1 in Diffuse Lower-Grade Glioma

2021 ◽  
Vol 20 ◽  
pp. 153303382110119
Author(s):  
Qiang Zhang ◽  
Xiao-Jun Liu ◽  
Yang Li ◽  
Xiao-Wei Ying ◽  
Lu Chen
Keyword(s):  
Overall Survival ◽  
Prognostic Value ◽  
High Expression ◽  
Lower Grade ◽  
Cox Regression Analysis ◽  
Kegg Pathways ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Go Terms ◽  
Genome Atlas

LncRNA SET-binding factor 2 (SBF2) antisense RNA1 (SBF2-AS1) has been proven to play an oncogenic role in various types of tumors, but the prognostic role of SBF2-AS1 in tumors, especially in diffuse lower-grade glioma (LGG), is still unclear. Here, we aimed to investigate the prognostic value of SBF2-AS1 in LGG. The LGG expression profiles from The Cancer Genome Atlas (TCGA, n = 524) and Chinese Glioma Genome Atlas (CGGA, n = 431) were mined by Kaplan-Meier analysis, Cox regression analysis, Chi-square test and GSEA analysis. Through Kaplan-Meier analysis, we found the prognosis of LGG patients with high expression of SBF2-AS1 were worse than that of patients with low expression (Log Rank P < 0.001). Cox analysis showed SBF2-AS1 was an independent prognostic factor for poorer overall survival in LGG ( P < 0.05). SBF2-AS1 was found to be significantly related to IDH mutation status and SBF2-AS1 was highly expressed in IDH wildtype group. GSEA analysis obtained a total of 126 GO terms and 6 KEGG pathways that were significantly enriched in SBF2-AS1 high expression phenotype (NOM P value < 0.05). We found these 126 GO terms and KEGG pathways were mainly related to immunity. In conclusion, lncRNA SBF2-AS1 expression is an immune-related lncRNA associated with unfavorable overall survival in LGG. SBF2-AS1 could be a reliable prognostic biomarker for patients with LGG.

scholarly journals A pan-cancer perspective analysis reveals the opposite prognostic significance of CD133 in lower grade glioma and papillary renal cell carcinoma

2021 ◽  
Vol 104 (2) ◽  
pp. 003685042110109
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Prognostic Factor ◽  
Prognostic Significance ◽  
Papillary Renal Cell Carcinoma ◽  
High Expression ◽  
Lower Grade ◽  
Cd133 Expression ◽  
The Poor ◽  
Lower Grade Glioma ◽  
Pan Cancer ◽  
Perspective Analysis

CD133 is a valuable prognostic marker in multiple types of cancer. However, the expression, methylation levels, and prognostic relevance of CD133 have not been evaluated in a pan-cancer perspective. The expression and methylation levels of CD133 across different types of cancer were determined using The Cancer Genome Atlas (TCGA) dataset. Univariate cox regression and Kaplan-Meier survival were used to determine the prognostic significance of CD133 expression and methylation. CD133 was highly expressed in papillary renal cell carcinoma (PRCC) or pancreatic adenocarcinoma (PAAD). Correspondingly, PAAD and PRCC had low CD133 methylation levels. Through pan-cancer perspective analysis, we found that CD133 high expression was a poor prognostic factor in lower grade glioma (LGG), while, CD133 high expression was a good prognostic factor in PRCC. Moreover, genes positively correlated with CD133 expression were associated with the poor clinical outcomes of LGG. In PRCC, genes negatively correlated with CD133 expression were correlated with the poor overall survival. Furthermore, CD133 expression levels were highly correlated with the CD133 methylation levels in LGG or PRCC. Correspondingly, CD133 hypermethylation was a good prognostic factor in LGG. On the contrary, CD133 hypomethylation was a good prognostic factor in PRCC. We also found that CD133 was highly expressed and hypomethylated in wild type IDH subgroup of LGG. CD133 was highly expressed and hypomethylated in low stages and type1 of PRCC. CD133 high expression and hypomethylation were bad prognostic factors in LGG, while, CD133 high expression and hypomethylation were good prognostic factors in PRCC.

scholarly journals Integrated Analysis of the Clinical and Molecular Characteristics of IDH Wild-Type Gliomas in the Chinese Glioma Genome Atlas

2021 ◽  
Author(s):  
Peng Wang ◽  
Yanwei Liu ◽  
Lin Zhi ◽  
Xiaoguang Qiu
Keyword(s):  
Genetic Information ◽  
Reduction Process ◽  
Progression Free Survival ◽  
Integrated Analysis ◽  
Molecular Characteristics ◽  
Lower Grade ◽  
Wild Type ◽  
Oxidation Reduction ◽  
Lower Grade Glioma ◽  
Genome Atlas

Abstract Purpose: Current studies and guidelines suggest that the biobehavior of IDH-wild type (IDH-wt) lower-grade glioma (LGG, WHO II-III) is similar to IDH-wt glioblastoma (GBM). However, differences in their clinical and molecular characteristics have not been reported. This study aimed to analyze the clinical and genetic information of gliomas with IDH-wt. Methods: Four hundred patients with IDH-wt were enrolled in the study (LGG = 176, GBM = 224), and their clinical and genetic information was collected from the Chinese Glioma Genome Atlas (CGGA). We conducted an analysis of this information between the two groups of patients and drew conclusions thereof. Results: The median age of the LGG patients was 42 (40–47) years, while that of the GBM patients was 51 (47–53) years (P < 0.05). GBM patients were more likely to undergo total resection (P < 0.05) and had fewer epileptic seizure symptoms (P < 0.01). The median overall survival (OS) was 51.87 months for the LGG patients and only 14.5 months for the GBM patients (P < 0.01). The median progression-free survival (PFS) was 37.6 months for the LGG patients and only 9.3 months for the GBM patients (P < 0.01). LGG patients were more prone to PETN mutations (P < 0.05). Transcriptome analysis showed that the differentially expressed genes in LGG patients were mainly enriched in metabolic pathways and pathways in cancer and in the function of signal transduction and positive regulation of GTPase activity, while in GBM patients, they were mainly enriched in the PI3K-Akt signaling pathway and in the functions of apoptotic process and oxidation-reduction process. Conclusions: Our data indicate that these two groups of patients should be re-evaluated and treated differently, despite both having IDH wild type.

scholarly journals Integrated Analysis of the Clinical and Molecular Characteristics of IDH Wild-Type Gliomas in the Chinese Glioma Genome Atlas

2021 ◽  
Vol 11 ◽  
Author(s):  
Peng Wang ◽  
Yanwei Liu ◽  
Lin Zhi ◽  
Xiaoguang Qiu
Keyword(s):  
Genetic Information ◽  
Reduction Process ◽  
Progression Free Survival ◽  
Integrated Analysis ◽  
Molecular Characteristics ◽  
Lower Grade ◽  
Wild Type ◽  
Oxidation Reduction ◽  
Lower Grade Glioma ◽  
Genome Atlas

PurposeCurrent studies and guidelines suggest that the biobehavior of IDH-wild type (IDH-wt) lower-grade glioma (LGG, WHO II-III) is similar to IDH-wt glioblastoma (GBM). However, differences in their clinical and molecular characteristics have not been reported. This study aimed to analyze the clinical and genetic information of gliomas with IDH-wt.Methods389 patients with IDH-wt were enrolled in the study (LGG=165, GBM=224), and their clinical and genetic information was collected from the Chinese Glioma Genome Atlas (CGGA). We conducted an analysis of this information between the two groups of patients and drew conclusions thereof.ResultsThe median age of the LGG patients was 42 (18–74) years, whereas that of the GBM patients was 51 (18–79) years (P &lt; 0.010). GBM patients were more likely to undergo total resection (P = 0.018) and had fewer epileptic seizure symptoms (P &lt; 0.001). The median overall survival (OS) was 55 months for the LGG patients and only 14.83 months for the GBM patients (P &lt; 0.01). The median progression-free survival (PFS) was 44 months for the LGG patients and only 9.767 months for the GBM patients (P &lt; 0.001). GBM patients were more prone to PETN mutations (P = 0.010). Transcriptome analysis showed that the differentially expressed genes in LGG patients were mainly enriched in metabolic pathways and pathways in cancer and in the function of signal transduction and positive regulation of GTPase activity, whereas in GBM patients, they were mainly enriched in the PI3K-Akt signaling pathway and in the functions of apoptotic process and oxidation-reduction process.ConclusionsOur data indicate that these two groups of patients should be re-evaluated and treated differently, despite both having IDH wild type.

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

scholarly journals Association Between Tumor Mutation Burden and Prognosis in Lower-Grade Glioma: An Exploratory Study 

2021 ◽  
Author(s):  
Di Cao ◽  
Jun Wang ◽  
Yan Lin ◽  
Guangwei Li
Keyword(s):  
Immune Cell ◽  
Differential Expression Analysis ◽  
Cell Infiltration ◽  
Lower Grade ◽  
Immune Cell Infiltration ◽  
Hub Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Lower Grade Glioma ◽  
Genome Atlas

Abstract Background: The therapeutic efficacy of immune checkpoint inhibitor therapy is highly influenced by tumor mutation burden (TMB). The relationship between TMB and prognosis in lower-grade glioma is still unclear. We aimed to explore the relationships and mechanisms between them in lower-grade glioma.Methods: We leveraged somatic mutation data from The Cancer Genome Atlas (TCGA). Clinical cases were divided into high- and low-TMB groups based on the median of TMB. Infiltrating immune cells were analyzed using CIBERSORT and differential expression analysis between the prognostic groups performed. The key genes were identified as intersecting between immune-related genes. Cox regression and survival analysis were performed on the intersecting genes. A total of 7 hub genes were identified. The effect of somatic copy number alterations (SCNA) of the hub genes on immune cell infiltration was analyzed using TIMER, which was used to determine the risk factors and immune infiltration status in LGG. Subsequently, based on hub genes, a TMB Prognosis Index (TMBPI) model was constructed to predict the risk in LGG patients. Besides, this model was validated using data from TCGA and Chinese Glioma Genome Atlas (CGGA).Results: High-TMB favored worse prognosis (P＜0.001) and macrophage infiltration was an independent risk factor (P＜0.001). In the high-TMB group (P=0.033, P=0.009), the proportion of macrophages M0 and M2 increased and monocytes decreased (P=0.006). Besides, the SCNA of the hub genes affected the level of immune cell infiltration by varying degrees among which IGF2BP3, NPNT, and PLA2G2A had a significant impact. The AUC of the ROC curve at 1-, 3- and 5-years were all above 0.74.Conclusions: This study implies that high-TMB correlated with unfavorable prognosis in lower-grade glioma. And high-TMB may have an impact on prognosis by changing tumor microenvironment, caused by the SCNAs of genes. The TMBPI model accurately predicted prognosis in LGG patients.

scholarly journals A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

2020 ◽  
Vol 78 (1) ◽  
pp. 34-38
Author(s):  
Burcu BITERGE-SUT
Keyword(s):  
Glioblastoma Multiforme ◽  
Malignant Gliomas ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Nonsense Mutations ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

scholarly journals CSIG-19. THE DEUBIQUITINASE BRCC3 LINKS ALT TELOMERES TO SUPPRESSION OF INNATE IMMUNITY IN IDH1-MUTANT GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii31-ii32
Author(s):  
Joydeep Mukherjee ◽  
Yongjian Tang ◽  
Tor-Christian Johanessen ◽  
Ajay Pandita ◽  
Shigeo Ohba ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Lower Grade ◽  
Astrocytoma Cells ◽  
Double Stranded Dna ◽  
Alternative Lengthening ◽  
Lower Grade Glioma ◽  
Exogenous Expression ◽  
Sting Pathway

Abstract Approximately 10% of tumors including all IDH1-mutant lower-grade glioma resolve telomeric shortening using Alternative Lengthening of Telomere (ALT) mechanism. Although the ALT process lengthens telomeres, it also generates small bits of extrachromosomal, telomere-containing DNA (ECTRs). These ECTRs can bind and activate cyclic GMP-AMP synthase (cGAS), the major cytosolic sensor of double-stranded DNA, which in turn can activate expression of stimulator of IFN genes (STING) and the interferon-based innate immune response. To limit the immune response, ALT cells inactivate the cGAS-STING pathway, although the mechanism by which this occurs is unknown. Here we show that the deubiquitinase BRCC3 links ALT telomeres to suppression of the cGAS-STING pathway and the innate immune response. Astrocytoma cells dependent on the ALT-mechanism (IDH1-mutant and ATRX-deficient genetically-modified human astrocytes and MGG119 PDX) contained ECTR and had reduced expression of the cGAS and the downstream components of the cGAS-STING pathway (STING, and IFN-β) relative to matched non-ALT (isogenic ATRX WT astrocytes and MGG152 PDX) cells lacking ECTRs. Decreased levels of cGAS in ALT cells were in turn associated with deubiquitiantion and destabilization of cGAS. The telomere-derived ECTR in ALT-dependent cells lacked two proteins normally found in ALT telomeres (TRF2 or PARP), but retained two other proteins, Mre11 and its binding partner, normally nuclear deubiquitinase BRCC3. Furthermore, either pharmacologic inhibition or genetic suppression of BRCC3 levels had no effect on ECTR levels but stabilized cGAS and activated the cGAS-STING pathway. This cGAS-mediated activation could be blocked by exogenous expression of WT BRCC3, but not by expression of a mutant BRCC3 incapable of deubiquitination. These results show that BRCC3 translocated along with ECTRs to the cytoplasm degrades cGAS and protects ALT-dependent cells from activating the innate immune response. The BRCC3-controlled cGAS-STING pathway may therefore represent a therapeutically targetable means to enhance the immune response in IDH1-mutant lower grade glioma.

Clinicopathological signature and prognostic value of RNA:m5C methyltransferases in gliomas

2020 ◽  
Author(s):  
Peng Wang ◽  
Kai Huang ◽  
Miaojing Wu ◽  
Qing Hu ◽  
Chuming Tao ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Score ◽  
Prognostic Value ◽  
Cox Regression ◽  
Roc Curves ◽  
Clinicopathological Features ◽  
Gene Set Enrichment Analysis ◽  
Consensus Clustering ◽  
Score Model ◽  
Genome Atlas

Abstract Background: Glioma is the most common primary intracranial tumor, accounting for the vast majority of intracranial malignant tumors. Aberrant expression of RNA:5-methylcytosine(m5C) methyltransferases has recently been the focus of research relating to the occurrence and progression of tumors. However, the prognostic value of RNA:m5C methyltransferases in glioma remains unclear. This study investigated RNA: m5C methyltransferase expression and defined its clinicopathological signature and prognostic value in gliomas. Methods: We systematically studied the RNA-sequence data of RNA:m5C methyltransferases underlying gliomas in the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets and identified different subtypes using Consensus clustering analysis. Gene Ontology (GO) and Gene Set Enrichment analysis (GSEA) was used to annotate the function of these genes. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm analyses were performed to construct the risk score model. Kaplan-Meier method and Receiver operating characteristic (ROC) curves were used to assess the overall survival of glioma patients. Additionally, Cox proportional regression model analysis was developed to address the connections between the risk scores and clinical factors. Results: Consensus clustering of RNA:m5C methyltransferases identified three clusters of gliomas with different prognostic and clinicopathological features. Meanwhile, Functional annotations demonstrated that RNA:m5C methyltransferases were significantly associated with the malignant progression of gliomas. Thereafter, five RNA:m5C methyltransferase genes were screened to construct a risk score model which can be used to predict not only overall survival but also clinicopathological features in gliomas. ROC curves revealed the significant prognostic ability of this signature. In addition, Multivariate Cox regression analyses indicated that the risk score was an independent prognostic factor for glioma outcome. Conclusion: We demonstrated the role of RNA:m5C methyltransferases in the initiation and progression of glioma. We have expanded on the understanding of the molecular mechanism involved, and provided a unique approach to predictive biomarkers and targeted therapy.

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