scholarly journals Pan-Cancer Analysis of Clinical Relevance via Telomere Maintenance Mechanism

2021 ◽  
Vol 22 (20) ◽  
pp. 11101
Author(s):  
Ji-Yong Sung ◽  
Jae-Ho Cheong
Keyword(s):  
Poor Prognosis ◽  
Cell Activation ◽  
Immune Cell ◽  
Metastatic Cancer ◽  
Telomerase Activity ◽  
Good Prognosis ◽  
Telomere Maintenance ◽  
The Cancer Genome Atlas ◽  
Maintenance Mechanism ◽  
Cancer Types

Understanding the telomere maintenance mechanism (TMM) in immortal cancer cells is vital for TMM-targeted therapies in clinical settings. In this study, we classified four telomere maintenance mechanisms into telomerase, ALT, telomerase + ALT, and non-defined telomere maintenance mechanism (NDTMM) across 31 cancer types using 10,704 transcriptomic datasets from The Cancer Genome Atlas. Our results demonstrated that approximately 50% of the total cohort displayed ALT activity with high telomerase activity in most cancer types. We confirmed significant patient prognoses according to distinct TMMs in six cancer types: adrenocortical carcinoma (ACC), PAAD, HNSC, SARC, GBM, and metastatic cancer. Patients with metastasis had a poor prognosis in the ALT group (p < 0.006) subjected to RAS protein signal transduction. Glioblastoma patients had poor prognosis in NDTMM (p < 0.0043) and showed high levels of myeloid leukocyte activation. Pancreatic adenocarcinoma (p < 0.04) and head and neck squamous cell carcinoma (p < 0.046) patients had a good prognosis in the ALT group with high immune cell activation. Furthermore, we showed that master transcriptional regulators might affect the selection of the TMM pathway and explained why different telomere maintenance mechanisms exist. Furthermore, they can be used to segregate patients and predict responders to different TMM-targeted therapeutics.

scholarly journals Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2207 ◽  
Author(s):  
Ji-Yong Sung ◽  
Hee-Woong Lim ◽  
Je-Gun Joung ◽  
Woong-Yang Park
Keyword(s):  
Telomerase Activity ◽  
Telomere Maintenance ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Alternative Lengthening ◽  
Significant Difference ◽  
Cancer Types ◽  
Antigen Presenting ◽  
Telomere Lengthening ◽  
Alt Activity

Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

scholarly journals Pan-Cancer Analysis of PIMREG as a Biomarker for the Prognostic and Immunological Role

2021 ◽  
Vol 12 ◽  
Author(s):  
Hua Zhu ◽  
Xinyao Hu ◽  
Yingze Ye ◽  
Zhihong Jian ◽  
Yi Zhong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Chemokine Receptors ◽  
Antigen Processing ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Lineage ◽  
Cell Receptor ◽  
The Cancer Genome Atlas ◽  
Cancer Types ◽  
Pan Cancer

Phosphatidylinositol binding clathrin assembly protein interacting mitotic regulator (PIMREG) localizes to the nucleus and can significantly elevate the nuclear localization of clathrin assembly lymphomedullary leukocythemia gene. Although there is some evidence to support an important action for PIMREG in the occurrence and development of certain cancers, currently no pan-cancer analysis of PIMREG is available. Therefore, we intended to estimate the prognostic predictive value of PIMREG and to explore its potential immune function in 33 cancer types. By using a series of bioinformatics approaches, we extracted and analyzed datasets from Oncomine, The Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia (CCLE) and the Human Protein Atlas (HPA), to explore the underlying carcinogenesis of PIMREG, including relevance of PIMREG to prognosis, microsatellite instability (MSI), tumor mutation burden (TMB), tumor microenvironment (TME) and infiltration of immune cells in various types of cancer. Our findings indicate that PIMREG is highly expressed in at least 24 types of cancer, and is negatively correlated with prognosis in major cancer types. In addition, PIMREG expression was correlated with TMB in 24 cancers and with MSI in 10 cancers. We revealed that PIMREG is co-expressed with genes encoding major histocompatibility complex, immune activation, immune suppression, chemokine and chemokine receptors. We also found that the different roles of PIMREG in the infiltration of different immune cell types in different tumors. PIMREG can potentially influence the etiology or pathogenesis of cancer by acting on immune-related pathways, chemokine signaling pathway, regulation of autophagy, RIG-I like receptor signaling pathway, antigen processing and presentation, FC epsilon RI pathway, complement and coagulation cascades, T cell receptor pathway, NK cell mediated cytotoxicity and other immune-related pathways. Our study suggests that PIMREG can be applied as a prognostic marker in a variety of malignancies because of its role in tumorigenesis and immune infiltration.

scholarly journals Comprehensive Analysis of the Immune Infiltrates of Pyroptosis in Kidney Renal Clear Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhuolun Sun ◽  
Changying Jing ◽  
Xudong Guo ◽  
Mingxiao Zhang ◽  
Feng Kong ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Carcinoma ◽  
Poor Prognosis ◽  
Immune Cell ◽  
Risk Model ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Renal Clear Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Risk Scores

Kidney renal clear cell carcinoma (KIRC) has long been identified as a highly immune-infiltrated tumor. However, the underlying role of pyroptosis in the tumor microenvironment (TME) of KIRC remains poorly described. Herein, we systematically analyzed the prognostic value, role in the TME, response to ICIs, and drug sensitivity of pyroptosis-related genes (PRGs) in KIRC patients based on The Cancer Genome Atlas (TCGA) database. Cluster 2, by consensus clustering for 24 PRGs, presented a poor prognosis, likely because malignancy-related hallmarks were remarkably enriched. Additionally, we constructed a prognostic prediction model that discriminated well between high- and low-risk patients and was further confirmed in external E-MTAB-1980 cohort and HSP cohort. By further analyzing the TME based on the risk model, higher immune cell infiltration and lower tumor purity were found in the high-risk group, which presented a poor prognosis. Patients with high risk scores also exhibited higher ICI expression, indicating that these patients may be more prone to profit from ICIs. The sensitivity to anticancer drugs that correlated with model-related genes was also identified. Collectively, the pyroptosis-related prognosis risk model may improve prognostic information and provide directions for current research investigations on immunotherapeutic strategies for KIRC patients.

scholarly journals Identification of a gene set correlated with immune status in ovarian cancer by transcriptome-wide data mining

2020 ◽  
Author(s):  
Lili Fan ◽  
Han Lei ◽  
Ying Lin ◽  
Zhengwei Zhou ◽  
Guang Shu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Cell ◽  
Good Prognosis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Survival Prognosis ◽  
Immune Activity ◽  
Gene Set ◽  
Immune Infiltration ◽  
Keywords Ovarian Cancer

Abstract Background : Ovarian cancer (OC) is a serious tumor disease in gynecology. Many papers have reported that high tumor mutational burden (TMB) can generate many neoantigens to result in a higher degree of tumor immune infiltration, so our study aims to predict the key molecules in OC immunotherapy by combined TMB with immunoactivity-related gene. Method: We divided OC cases into two groups: the low & high TMB group hinged on the somatic mutation data from the Cancer Genome Atlas (TCGA). We also used single-sample gene set enrichment analysis (ssGSEA) scores of immune cell types to conduct unsupervised clustering of OC patients in the TCGA cohort and some of them were defined as the low & high immunity group. Besides, to further understand the function of these genes, we conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, protein-protein interaction network, survival prognosis analysis and immune infiltration analysis. Finally, the effects on prognosis and immunotherapy in OC patients were explored by the Group on Earth Observations verification the patients' responses to immunotherapy. Results: We found that the higher the TMB was associated with the higher OC grades. Moreover, both high TMB and high immunity were significantly correlated with a good prognosis of OC. Then, 14 up-regulated differential expression genes (Up-DEGs) that were closely related to the prognosis of OC patients were screened according to the high TMB group and the high immunity group. Next, pathway analysis revealed that Up-DGEs were mainly involved in immune response and T cell proliferation. Finally, four genes had a good prognosis and were validated in the GEO dataset which included CXCL13, FCRLA, PLA2G2D, and MS4A1. We also identified that four genes had a good prognosis in melanoma patients treated with anti-PD-L1 and anti-CTLA-4 in the TIDE database. Conclusion: High TMB can promote immune cell infiltration and increases immune activity. And our analysis also demonstrated that the higher the TMB, the higher the immune activity, the better the prognosis of OC. Altogether, we found that CXCL13, FCRLA, PLA2G2D, and MS4A1 may be biomarkers for OC immunotherapy. Keywords: ovarian cancer, TMB, immune cells infiltration, survival prognosis.

scholarly journals ASF1B Promotes Oncogenesis in Lung Adenocarcinoma and Other Cancer Types

2021 ◽  
Vol 11 ◽  
Author(s):  
Wencheng Zhang ◽  
Zhouyong Gao ◽  
Mingxiu Guan ◽  
Ning Liu ◽  
Fanjie Meng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Tumor Promoter ◽  
Regulatory Subunit ◽  
Cell Cycle Distribution ◽  
Cancer Type ◽  
Dependent Manner ◽  
Cancer Types

Anti-silencing function 1B histone chaperone (ASF1B) is known to be an important modulator of oncogenic processes, yet its role in lung adenocarcinoma (LUAD) remains to be defined. In this study, an integrated assessment of The Cancer Genome Atlas (TCGA) and genotype-tissue expression (GTEx) datasets revealed the overexpression of ASF1B in all analyzed cancer types other than LAML. Genetic, epigenetic, microsatellite instability (MSI), and tumor mutational burden (TMB) analysis showed that ASF1B was regulated by single or multiple factors. Kaplan-Meier survival curves suggested that elevated ASF1B expression was associated with better or worse survival in a cancer type-dependent manner. The CIBERSORT algorithm was used to evaluate immune microenvironment composition, and distinct correlations between ASF1B expression and immune cell infiltration were evident when comparing tumor and normal tissue samples. Gene set enrichment analysis (GSEA) indicated that ASF1B was associated with proliferation- and immunity-related pathways. Knocking down ASF1B impaired the proliferation, affected cell cycle distribution, and induced cell apoptosis in LUAD cell lines. In contrast, ASF1B overexpression had no impact on the malignant characteristics of LUAD cells. At the mechanistic level, ASF1B served as an indirect regulator of DNA Polymerase Epsilon 3, Accessory Subunit (POLE3), CDC28 protein kinase regulatory subunit 1(CKS1B), Dihydrofolate reductase (DHFR), as established through proteomic profiling and Immunoprecipitation-Mass Spectrometry (IP-MS) analyses. Overall, these data suggested that ASF1B serves as a tumor promoter and potential target for cancer therapy and provided us with clues to better understand the importance of ASF1B in many types of cancer.

scholarly journals KDM1A Identified as a Potential Oncogenic Driver and Prognostic Biomarker via Multi-Omics Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Lingyue Li ◽  
Yiyu Wang ◽  
Yuan Mou ◽  
Hao Wu ◽  
Ye Qin
Keyword(s):  
Immune Cell ◽  
Prognostic Biomarker ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Th2 Cells ◽  
Th1 Cell ◽  
Transport Pathways ◽  
Epigenetic Factor ◽  
Omics Analysis ◽  
Cancer Types

Background. Lysine-specific demethylase 1A (KDM1A) is a histone demethylation enzyme and a crucial epigenetic factor for multiple pathological pathways that mediate carcinogenesis and immunogenicity. Although increasing evidence supposes the association between KDM1A and cancers, no systematic multi-omics analysis of KDM1A is available. Methods. We systematically evaluated the KDM1A expression of various cancer and normal tissues and the unique relationship between KDM1A expression and prognosis of cancer cases based on The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The genetic variations, phosphorylation, and DNA methylation of KDM1A were analyzed via various tools. We further analyzed the correlation of KDM1A expression and fibroblasts and immune cell infiltration score of TCGA samples via TIMER2.0. Results. KDM1A was highly expressed in 17 types of total 33 cancers, while it expressed low levels in only 4 cancers. High KDM1A expression was associated with worse survival status in various cancers. KDM1A expression was positively correlated with the cancer-associated fibroblasts and myeloid-derived suppressor cells infiltration levels in most cancer types. Additionally, KDM1A in most cancer types was negatively correlated with Th1 cell infiltration and positively correlated with Th2 cells. Moreover, spliceosome, cell cycle, and RNA transport pathways were involved in the functional mechanisms of KDM1A via enrichment analysis. Conclusions. Our study describes the epigenetic factor KDM1A as an oncogene and prognostic biomarker. Our findings provide valuable guidance for further analysis of KDM1A function in pathogenesis and potential clinical treatment.

scholarly journals Prognostic and immune regulating roles of YIF1B in Pan-Cancer: a potential target for both survival and therapy response evaluation

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Jun Liu ◽  
Zheng Chen ◽  
Pingsen Zhao ◽  
Wenli Li
Keyword(s):  
Tumor Growth ◽  
Membrane Trafficking ◽  
Serotonin Receptor ◽  
Immune Cell ◽  
Therapy Response ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Poor Overall Survival ◽  
Cancer Types ◽  
Spearman Test

Abstract The neurotransmitter, serotonin has emerged as a tumor growth factor and immune response regulator through complex signaling pathways. Yip1 Interacting Factor Homolog B (YIF1B) is a membrane protein involved in serotonin receptor (HTR) membrane trafficking and signal transmission in neuropathy. Participation of YIF1B in serotonin-induced tumor growth and immune regulation has not been previously investigated. Data for analysis of YIF1B mRNA expression were downloaded from the website portals: The Cancer Genome Atlas (TCGA), GTEx, Cancer Cell Line Encyclopedia (CCLE) and International Cancer Genome Consortium (ICGC), including clinical and mutational information. Survival analysis included the Kaplan–Meier method for calculation of the cumulative incidence of the survival event and the log rank method for comparison of survival curves between groups. Infiltration levels of immune cells were calculated and correlated with YIF1B expression using the Spearman correlation test to evaluate significance. Further correlation analyses between YIF1B expression and mutation indicators such as tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) were also examined by the Spearman test. YIF1B expression was elevated in most cancer types and this high expression was indicative of poor overall survival (OS) and death-specific survival. In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression. There was a positive relationship between YIF1B expression and immune cell infiltration in several cancer types, and YIF1B also positively correlated with TMB, MSI, and methylation in some cancer types, linking its expression to possible evaluation of therapy response. The bioinformatics analyses have, therefore, established YIF1B as a good biomarker for prognostic and therapeutic evaluation.

scholarly journals Dynamin 3 Gene as a Tumor Suppressor and an Independent Predictive Factor of Poor Prognosis in Patients with Gastric Cancer

2021 ◽  
Author(s):  
Ru-Hong Tu ◽  
Jian-Xian Lin ◽  
Jian-Wei Xie ◽  
Jia-Bin Wang ◽  
Jun Lu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Predictive Factor ◽  
Poor Prognosis ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Independent Predictive Factor ◽  
Stomach Adenocarcinoma ◽  
Low Expression

Abstract Gastric cancer is a leading cause of death from malignant tumors worldwide. With the development of genome sequencing technology, an increasing number of key driver genes and tumor suppressors have been discovered. Some studies have suggested that Dynamin 3 (DNM3) is a novel tumor suppressor; however, the role of DNM3 in malignancy remains unclear. We performed a systematic analysis using The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohorts, and 160 patients with stomach adenocarcinoma at Fujian Medical University Union Hospital (FJMUUH) (48 quantitative PCR [qPCR] and 112 immunohistochemistry). DNM3 expression was found to be downregulated in gastric cancer compared to that in paraneoplastic tissue. Low expression of DNM3 was mainly associated with DNM3 promoter hypermethylation status. Low expression of DNM3 can upregulate the tumor cell cycle and oxidative phosphorylation process and downregulate immune regulation, and Th17 and Th2 immune cell infiltration was increased in patients with lower expression of DNM3. Patients with a lower DNM3 expression had a higher rate of lymph node metastasis and poor prognosis. In summary, DNM3 is a tumor suppressor and an independent predictive factor of poor prognosis that regulates the cell cycle and immunosuppression in the tumor microenvironment in gastric cancer via methylation.

scholarly journals A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling Peng ◽  
Jisheng Li ◽  
Jie Wu ◽  
Bin Xu ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Immunity ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Poor Overall Survival ◽  
Atpase Subunit ◽  
Human Cancers ◽  
Cancer Types

BackgroundSMARCA4, the essential ATPase subunit of SWI/SNF chromatin remodeling complex, regulates transcription through the control of chromatin structure and is increasingly thought to play significant roles in human cancers. This study aims to explore the potential role of SMARCA4 with a view to providing insights on pathologic mechanisms implicated here.MethodsThe potential roles of SMARCA4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. The expression difference, mutation and phosphorylation status, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), and immune cell infiltration related to SMARCA4 were analyzed.ResultsHigh expression levels of SMARCA4 were observed in most cancer types. SMARCA4 expression in tumor samples correlates with poor overall survival in several cancers. Lung adenocarcinoma cases with altered SMARCA4 showed a poorer prognosis. Enhanced phosphorylation levels of S613, S695, S699, and S1417 were observed in several tumors, including breast cancer. SMARCA4 correlated with tumor immunity and associated with different immune cells and genes in different cancer types. TMB, MSI, MMR, and DNA methylation correlated with SMARCA4 dysregulation in cancers. SMARCA4 expression was negatively associated with CD8+ T-cell infiltration in several tumors. Furthermore, the SWI/SNF superfamily-type complex and ATPase complex may be involved in the functional mechanisms of SMARCA4, albeit these data require further confirmation.ConclusionsOur study offers a comprehensive understanding of the oncogenic roles of SMARCA4 across different tumors. SMARCA4 may correlate with tumor immunity.

scholarly journals Systematic Pan-Cancer Analysis Identifies TREM2 as an Immunological and Prognostic Biomarker

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Cheng ◽  
Xiaowei Wang ◽  
Kechao Nie ◽  
Lin Cheng ◽  
Zheyu Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Cell ◽  
Lung Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Immunoglobulin Superfamily ◽  
Cancer Types ◽  
Pan Cancer

Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although increasing evidence supports a vital role for TREM2 in tumorigenesis of some cancers, no systematic pan-cancer analysis of TREM2 is available. Thus, we aimed to explore the prognostic value, and investigate the potential immunological functions, of TREM2 across 33 cancer types. Based on datasets from The Cancer Genome Atlas, and the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, and Human Protein Atlas, we employed an array of bioinformatics methods to explore the potential oncogenic roles of TREM2, including analyzing the relationship between TREM2 and prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration of different tumors. The results show that TREM2 is highly expressed in most cancers, but present at low levels in lung cancer. Further, TREM2 is positively or negatively associated with prognosis in different cancers. Additionally, TREM2 expression was associated with TMB and MSI in 12 cancer types, while in 20 types of cancer, there was a correlation between TREM2 expression and DNA methylation. Six tumors, including breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, and stomach adenocarcinoma, were screened out for further study, which demonstrated that TREM2 gene expression was negatively correlated with infiltration levels of most immune cells, but positively correlated with infiltration levels of M1 and M2 macrophages. Moreover, correlation with TREM2 expression differed according to T cell subtype. Our study reveals that TREM2 can function as a prognostic marker in various malignant tumors because of its role in tumorigenesis and tumor immunity.

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