scholarly journals Association of RYR2 Mutation with Tumor Mutation Burden, Prognosis and Antitumor Immunity in Patients with Esophageal Adenocarcinoma

2021 ◽  
Author(s):  
Zaoqu Liu ◽  
Long Liu ◽  
Chunguang Guo ◽  
Libo Wang ◽  
Zhaonan Li ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Immune Cell ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Cancer Genome Atlas ◽  
Additional Reference

Abstract BackgroundEsophageal adenocarcinoma (EAC) remains a leading cause of cancer-related deaths worldwide, and demonstrates a predominant rising incidence in Western countries. Recently, immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in EAC thus far been limited to a small fraction of patients. MethodsUsing somatic mutations data of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), we delineated somatic mutation landscape of EAC patients from US and England. Bioinformatics algorithms were utilized to perform function annotation, immune cell infiltration analysis, and immunotherapy response assessment.ResultsWe found that RYR2 was a common frequently mutated gene (FMG) in both cohorts, and patients with RYR2 mutation suggested higher tumor mutation burden (TMB), better prognosis, and superior expression of immune checkpoints. Moreover, RYR2 mutation upregulated the signaling pathways implicated in immune response and enhanced antitumor immunity in EAC. Multiple bioinformatics algorithms for assessing immunotherapy response demonstrated that patients with RYR2 mutation might benefit more from immunotherapy. In order to provide additional reference for antitumor therapy of different RYR2 status, we identified nine latent antitumor drugs associated with RYR2 status in EAC. ConclusionsThis study reveals a novel gene whose mutation could be served as a potential biomarker for prognosis, TMB, and immunotherapy of EAC patients.

scholarly journals Association of RYR2 Mutation With Tumor Mutation Burden, Prognosis, and Antitumor Immunity in Patients With Esophageal Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Zaoqu Liu ◽  
Long Liu ◽  
Dechao Jiao ◽  
Chunguang Guo ◽  
Libo Wang ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Somatic Mutation ◽  
Antitumor Immunity ◽  
Immune Cell ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker

Background: Esophageal adenocarcinoma (EAC) remains a leading cause of cancer-related deaths worldwide and demonstrates a predominant rising incidence in Western countries. Recently, immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, with the benefit in EAC thus far been limited to a small fraction of patients.Methods: Using somatic mutation data of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium, we delineated the somatic mutation landscape of EAC patients from US and England. Based on the expression data of TCGA cohort, multiple bioinformatics algorithms were utilized to perform function annotation, immune cell infiltration analysis, and immunotherapy response assessment.Results: We found that RYR2 was a common frequently mutated gene in both cohorts, and patients with RYR2 mutation suggested higher tumor mutation burden (TMB), better prognosis, and superior expression of immune checkpoints. Moreover, RYR2 mutation upregulated the signaling pathways implicated in immune response and enhanced antitumor immunity in EAC. Multiple bioinformatics algorithms for assessing immunotherapy response demonstrated that patients with RYR2 mutation might benefit more from immunotherapy. In order to provide additional reference for antitumor therapy of different RYR2 status, we identified nine latent antitumor drugs associated with RYR2 status in EAC.Conclusion: This study reveals a novel gene whose mutation could be served as a potential biomarker for prognosis, TMB, and immunotherapy of EAC patients.

scholarly journals Comparison of commonly used solid tumor targeted gene sequencing panels for estimating tumor mutation burden shows analytical and prognostic concordance within the cancer genome atlas cohort

2020 ◽  
Vol 8 (1) ◽  
pp. e000613
Author(s):  
Nicholas Bevins ◽  
Shulei Sun ◽  
Zied Gaieb ◽  
John A Thorson ◽  
Sarah S Murray
Keyword(s):  
Solid Tumor ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Tumor Mutation Burden ◽  
Whole Exome ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Gene Panels ◽  
The Impact ◽  
Genome Atlas

BackgroundTumor mutation burden (TMB) is a biomarker frequently reported by clinical laboratories, which is derived by quantifying of the number of single nucleotide or indel variants (mutations) identified by next-generation sequencing of tumors. TMB values can inform prognosis or predict the response of a patient’s tumor to immune checkpoint inhibitor therapy. Methods for the calculation of TMB are not standardized between laboratories, with significant variables being the gene content of the panels sequenced and the inclusion or exclusion of synonymous variants in the calculations. The impact of these methodological differences has not been investigated and the concordance of reported TMB values between laboratories is unknown.MethodsSequence variant lists from more than 9000 tumors of various types were downloaded from The Cancer Genome Atlas. Variant lists were filtered to include only appropriate variant types (ie, non-synonymous only or synonymous and non-synonymous variants) within the genes found in five commonly used targeted solid tumor gene panels as well as an in-house gene panel. Calculated TMB was paired with corresponding overall survival (OS) data of each patient.ResultsRegression analysis indicates high concordance of TMB as derived from the examined panels. TMB derived from panels was consistently and significantly lower than that derived from a whole exome. TMB, as derived from whole exome or the examined panels, showed a significant correlation with OS in the examined data.ConclusionsTMB derived from the examined gene panels was analytically equivalent between panels, but not between panels and whole-exome sequencing. Correlation between TMB and OS is significant if TMB method-specific cut-offs are used. These results suggest that TMB values, as derived from the gene panels examined, are analytically and prognostically equivalent.

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽  
2020 ◽  
Author(s):  
Qijie Zhao ◽  
Jinan Guo ◽  
Yueshui Zhao ◽  
Jing Shen ◽  
Parham Jabbarzadeh Kaboli ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Comprehensive Analysis ◽  
The Cancer Genome Atlas ◽  
Gastrointestinal Cancers ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

scholarly journals Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhuomao Mo ◽  
Daiyuan Liu ◽  
Dade Rong ◽  
Shijun Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
Cox Regression ◽  
Cancer Genome ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Immune Cell Infiltration ◽  
Immunosuppressive Microenvironment

Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC.Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score.Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts.Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.

scholarly journals Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

2019 ◽  
Author(s):  
Lin Li ◽  
Mengyuan Li ◽  
Xiaosheng Wang
Keyword(s):  
Antitumor Immunity ◽  
Colon Adenocarcinoma ◽  
Joint Effect ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Negative Role ◽  
Stomach Adenocarcinoma ◽  
Cancer Types

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

scholarly journals A hypoxia-related signature for clinically predicting diagnosis, prognosis and immune microenvironment of hepatocellular carcinoma patients.

2020 ◽  
Author(s):  
Baohui Zhang ◽  
Bufu Tang ◽  
Jianyao Gao ◽  
Jiatong Li ◽  
Lingming Kong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
High Risk Group ◽  
Cancer Genome ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Diagnostic Model ◽  
Potential Biomarker

Abstract Background Hypoxia plays an indispensable role in the development of hepatocellular carcinoma (HCC). However, there are few studies on the application of hypoxia molecules in the prognosis predicting of HCC. We aimed to identify the hypoxia-related genes in HCC and construct reliable models for diagnosis, prognosis and recurrence of HCC patients as well as exploring the potential mechanism.Methods Differentially expressed genes (DEGs) analysis was performed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database and four clusters were determined by a consistent clustering analysis. Three DEGs closely related to overall survival（OS）were identified using Cox regression and LASSO analysis and the hypoxia-related signature was developed and validated in TCGA and International Cancer Genome Consortium (ICGC) database. Then the Gene Set Enrichment Analysis (GSEA) was performed to explore signaling pathways regulated by the signature and the CIBERSORT was used for estimating the fractions of immune cell types.Results A total of 397 hypoxia-related DEGs were detected and three genes (PDSS1, CDCA8 and SLC7A11) were selected to construct a prognosis, recurrence and diagnosis model. Then patients were divided into high- and low-risk groups. Our hypoxia-related signature was significantly associated with worse prognosis and higher recurrence rate. The diagnostic model also accurately distinguished HCC from normal samples and nodules. Furthermore, the hypoxia-related signature could positively regulate immune response and the high-risk group had higher fractions of macrophages, B memory cells and follicle-helper T cells, and exhibited higher expression of immunocheckpoints such as PD1and PDL1.Conclusions Altogether, our study showed that hypoxia-related signature is a potential biomarker for diagnosis, prognosis and recurrence of HCC, and it provided an immunological perspective for developing personalized therapies.

scholarly journals Comprehensive Analysis of m6A Regulators Characterized by the Immune Cell Infiltration in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy and Chemotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiqiang Yang ◽  
Xiaoping Ming ◽  
Shuo Huang ◽  
Minlan Yang ◽  
Xuhong Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Cell ◽  
Comprehensive Evaluation ◽  
Principal Component ◽  
Response To Therapy ◽  
The Cancer Genome Atlas ◽  
Mutation Burden ◽  
Number Variation ◽  
Clinical Benefits ◽  
Cancer Genome Atlas

BackgroundN6-Methyladenosine (m6A), which is a prevalent regulator of mRNA expression, has gathered increasing study interests. Though the role of m6A as being important in many biological processes (such as growth and proliferation of cancers) has been well documented, its potential role in tumor immune microenvironment (TIME) has rarely been analyzed.MethodsWe downloaded RNA expression, single nucleotide polymorphism (SNP), and copy number variation (CNV) data from The Cancer Genome Atlas (TCGA). We then curated 21 m6A regulators and clustered patients into three m6A subtypes and m6A-related gene subtypes and compared them based on overall survival (OS). The combination of CIBERSORT as well as ssGSEA quantified the infiltration levels of immune cells and immune-related functions. The m6A scores were determined by using principal component analysis (PCA) algorithm. Furthermore, we evaluate the correlation of m6A regulators with immune and response to therapy.ResultsThree m6A clusters were identified based on the TCGA-HNSCC cohort, and there were significant associations among them in overall outcomes and caner-related pathways. We found that three m6A clusters were consistent with three phenotypes: immune-inflamed, immune-dessert, and immune-excluded. HNSCC patients were divided into high– and low–m6A score groups based on the cutoff of m6A score. Patients with lower m6A score had better overall survival outcome. Further analysis indicated that patients with higher m6A score presented higher tumor mutation burden (TMB). In addition, patients in low–m6A score subgroup had high chemotherapeutics sensitivity. GEO cohort confirmed patients with low m6A score demonstrated significant overall survival advantages and clinical benefits. Low m6A score carry an increased neoantigen load, eliciting a response to immunotherapy, and its value in predicting survival outcomes of immunotherapy was also confirmed in three anti-PD-1 cohorts.ConclusionsOur study demonstrated that m6A regulators are closely related to TIME and the m6A score was an effective prognostic biomarker and predictive indicator for immunotherapy and chemotherapeutics. Comprehensive evaluation of m6A regulators in tumors will extend our understanding of TIME and effectively guide increasing study investigations on immunotherapy and chemotherapy strategies for HNSCC.

scholarly journals An miRNA signature associated with tumor mutation burden in endometrial cancer

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Hongyu Zhou ◽  
Lihua Chen ◽  
Mei Qin ◽  
Yajie Lei ◽  
Tianjiao Li ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Mirna Signature ◽  
Training Set ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Validation Set ◽  
Brca1 Brca2 ◽  
Selection Operator

Abstract Tumor mutation burden (TMB) is an essential biomarker to predict immunotherapy response. TMB measurement was mainly evaluated by whole-exome sequencing (WES), which was costly and difficult to be widely applied. In the present study, we aimed to establish and validate a miRNA signature to predict TMB level in endometrial cancer using The Cancer Genome Atlas (TCGA) database. MiRNA expression and somatic mutation profiles of uterine corpus endometrial carcinoma (UCEC) were downloaded from TCGA database. Total 518 patients with UCEC were randomly classified into training set (n=311) and validation set (n=207). Thirty-five differentially expressed miRNAs between high-TMB and low-TMB group were identified in training set. Least absolute shrinkage and selection operator (LASSO) method was performed to select out 26 miRNAs to establish the optimal signature. The accuracy of the miRNA signature for predicting TMB level was 0.833 for training set, 0.749 for validation set and 0.799 for total set. Moreover, the miRNA signature had significant correlation with immune checkpoints related genes (PD-1, PD-L1, CTLA-4) and mismatch repair related genes (BRCA1, BRCA2, MLH1, MSH6) expression. In conclusion, this miRNA signature could predict TMB level in endometrial cancer and might have some merits in providing guidance for immunotherapy in endometrial cancer.

Expression of DUSP4 transcript variants as a potential biomarker for colorectal cancer

2020 ◽  
Vol 14 (8) ◽  
pp. 639-650
Author(s):  
Tatiana Varela ◽  
Vincent Laizé ◽  
Natércia Conceição ◽  
Paulo Caldeira ◽  
Ana Marreiros ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Kras Mutations ◽  
Normal Tissues ◽  
Potential Biomarker ◽  
Tumor Stages ◽  
Cancer Genome Atlas ◽  
Poorly Differentiated ◽  
Genome Atlas

Aim: To provide novel data on the expression of DUSP4 transcripts in colorectal cancer (CRC) tissues and to explore their potential as biomarkers. Materials & methods: DUSP4 transcripts expression was determined by quantitative real-time PCR in tissues from 28 CRC patients. Their association with clinicopathological factors and survival analysis was performed. Data from 380 CRC patients available at The Cancer Genome Atlas project were also analyzed. Results: All transcripts were overexpressed in CRC tissues. Variant X1 was the most upregulated and associated with KRAS mutations and poorly differentiated tumor. Overexpression of DUSP4 transcripts could distinguish all tumor stages from normal tissues. Similar results were found in The Cancer Genome Atlas cohort. Conclusion: DUSP4 transcripts have the potential to serve as diagnostic biomarkers for CRC, particularly variant X1.

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