scholarly journals Significance of tumor mutation burden and immune infiltration in thymic epithelial tumors

2021 ◽  
Author(s):  
Zi‐Ming Wang ◽  
Qi‐Rong Xu ◽  
David Kaul ◽  
Mahmoud Ismail ◽  
Harun Badakhshi
Keyword(s):  
Thymic Epithelial Tumors ◽  
Tumor Mutation Burden ◽  
Immune Infiltration ◽  
Epithelial Tumors ◽  
Mutation Burden

scholarly journals ­­Prognostic analysis of tumor mutation burden combined with immune infiltration of Thymic epithelial tumors

2020 ◽  
Author(s):  
Pinglang Ruan ◽  
Dan Liu ◽  
Lili Wang ◽  
Ling Qin ◽  
Yurong Tan
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Thymic Epithelial Tumors ◽  
Tumor Mutation Burden ◽  
Immune Genes ◽  
Immune Infiltration ◽  
Epithelial Tumors ◽  
Mutation Burden

Abstract Background: Thymic epithelial tumors (TETs) are uncommon neoplasms with poor prognosis and limited effective therapeutic options. This study aims to investigate the prognosis of tumor mutation burden (TMB) and the potential association with immune infiltrates in TETs. Methods: Tumor mutation burden (TMB) was calculated using Maftools package and the samples were classified into high-TMB and low- TMB groups. Differentially expressed genes (DEGs) combined with immune cell infiltration and survival rate were analyzed between the low-TMB and high-TMB groups.Results: Single nucleotide polymorphism (SNP) occurred more frequently than insertion or deletion, and C>T was the most common single nucleotide variants (SNV) in TETs. The results of Kaplan–Meier curve indicated that a high TMB was associated with worse clinical outcomes of TETs. Moreover, 3 hub immune genes associated with immune infiltration were significantly associated with prognosis. Besides, the TMB-related signature (TMBRS) model based on the three hub immune genes possessed good predictive value with area under curve (AUC) 0.729, and patients with higher TMBRS scores showed worse TETs outcomes. In addition, infiltration levels of native CD4+ T cell, activated memory CD4+ T cell and follicular helper T cells in low-TMB group were higher than those in high-TMB group, which were correlated positively with prognosis of TETs. Conclusion: TETs patients with low TMB have better prognosis than those with high TMB, and TMB might affect the development of TETs by regulating immune infiltration.

Exploration of Tumor Mutation Burden Combined with Immune Infiltrates in the Prognosis of Lung Adenocarcinoma

2021 ◽  
Author(s):  
Zhenyu Zhao ◽  
Boxue He ◽  
Qidong Cai ◽  
Pengfei Zhang ◽  
Xiong Peng ◽  
...  
Keyword(s):  
High Risk ◽  
Lung Adenocarcinoma ◽  
Clinical Application ◽  
Risk Group ◽  
High Risk Group ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Immune Signature ◽  
Immune Infiltration ◽  
Mutation Burden

Abstract Background: Lung adenocarcinoma (LUAD) accounts for a majority of cancer-related deaths worldwide annually. A recent study shows that immunotherapy is an effective method of LUAD treatment, and tumor mutation burden (TMB) was associated with the immune microenvironment and affected the immunotherapy. Exploration of the gene signature associated with tumor mutation burden and immune infiltrates in predicting prognosis in lung adenocarcinoma in this study, we explored the correlation of TMB with immune infiltration and prognosis in LUAD.Materials and Methods: In this study, we firstly got mutation data and LUAD RNA-Seq data of the LUAD from The Cancer Genome Atlas (TCGA), and according to the TMB we divided the patients into high/low-TMB levels groups. The gene ontology (GO) pathway enrichment analysis and KOBAS-Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were utilized to explore the molecular function of the differentially expressed genes (DEGs) between the two groups. The function enrichment analyses of DEGs were related to the immune pathways. Then, the ESTIMATE algorithm, CIBERSORT, and ssGSEA analysis were utilized to identify the relationship between TMB subgroups and immune infiltration. According to the results, Venn analysis was utilized to select the immune-related genes in DEGs. Univariate and Lasso Cox proportional hazards regression analyses were performed to construct the signature which positively associated with the immune infiltration and affected the survival. Finally, we verified the correlation between the signature and immune infiltration. Result: The exploration of the immune infiltration suggested that high-TMB subgroups positively associated with the high level of immune infiltration in LUAD patients. According to the TMB-related immune signature, the patients were divided into High/Low-risk groups, and the high-risk group was positively associated with poor prognostic. The results of the PCA analysis confirmed the validity of the signature. We also verified the effectiveness of the signature in GSE30219 and GSE72094 datasets. The ROC curves and C-index suggested the good clinical application of the TMB-related immune signature in LUAD prognosis. Another result suggested that the patients of the high-risk group were positively associated with higher TMB levels, PD-L1expression, and immune infiltration levels.Conclusion: In conclusion, our signature provides potential biomarkers for studying aspects of the TMB in LUAD such as TMB affected immune microenvironment and prognosis. This signature may provide some biomarkers which could improve the biomarkers of PD-L1 immunotherapy response and were inverted for the clinical application of the TMB in LUAD. LUAD male patients with higher TMB-levels and risk scores may benefit from immunotherapy. The high-risk patients along with higher PD-L1 expression of the signature may suitable for immunotherapy and improve their survival by detecting the TMB of LUAD.

scholarly journals Identification of Prognostic Biomarkers of Cutaneous Melanoma Based on Analysis of Tumor Mutation Burden

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jiaqiong Lin ◽  
Yan Lin ◽  
Zena Huang ◽  
Xiaoyong Li
Keyword(s):  
Cutaneous Melanoma ◽  
Prognostic Model ◽  
Cox Regression ◽  
Risk Group ◽  
Predictive Biomarkers ◽  
Tumor Mutation Burden ◽  
Skin Development ◽  
Cox Regression Analysis ◽  
Immune Infiltration ◽  
Mutation Burden

Background. Immunotherapy offers a novel approach for the treatment of cutaneous melanoma, but the clinical efficiency varies for individual patients. In consideration of the high cost and adverse effects of immunotherapy, it is essential to explore the predictive biomarkers of outcomes. Recently, the tumor mutation burden (TMB) has been proposed as a predictive prognosticator of the immune response. Method. RNA-seq and somatic mutation datasets of 472 cutaneous melanoma patients were downloaded from The Cancer Genome Atlas (TCGA) database to analyze mutation type and TMB. Differently expressed genes (DEGs) were identified for functional analysis. TMB-related signatures were identified via LASSO and multivariate Cox regression analysis. The association between mutants of signatures and immune cells was evaluated from the TIMER database. Furthermore, the Wilcox test was applied to assess the difference in immune infiltration calculated by the CIBERSORT algorithm in risk groupings. Results. C>T substitutions and TTN were the most common SNV and mutated gene, respectively. Patients with low TMB presented poor prognosis. DEGs were mainly implicated in skin development, cell cycle, DNA replication, and immune-associated crosstalk pathways. Furthermore, a prognostic model consisting of eight TMB-related genes was developed, which was found to be an independent risk factor for treatment outcome. The mutational status of eight TMB-related genes was associated with a low level of immune infiltration. In addition, the immune infiltrates of CD4+ and CD8+ T cells, NK cells, and M1 macrophages were higher in the low-risk group, while those of M0 and M2 macrophages were higher in the high-risk group. Conclusion. Our study demonstrated that a higher TMB was associated with favorable survival outcome in cutaneous melanoma. Moreover, a close association between prognostic model and immune infiltration was identified, providing a new potential target for immunotherapy.

Increased neutrophil infiltration and lower prevalence of tumor mutation burden and microsatellite instability are hallmarks of RAS mutant colorectal cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3563-3563
Author(s):  
Emil Lou ◽  
Yasmine Baca ◽  
Joanne Xiu ◽  
Andrew Nelson ◽  
Subbaya Subramanian ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Neutrophil Infiltration ◽  
Cell Fraction ◽  
Colorectal Cancers ◽  
Tumor Mutation Burden ◽  
Immune Infiltration ◽  
Mutation Burden

3563 Background: The tumor microenvironment (TME) of colorectal cancers (CRC) is modulated by oncogenic drivers such as KRAS. The TME comprises a broad landscape of immune infiltration. How tumor genomics associates with the immune cell landscape is less known. We aim to characterize immune cell types in RAS wild-type (WT) and mutant (MT) CRC, and to examine the prevalence of immuno-oncologic (IO) biomarkers (e.g. tumor mutation burden (TMB), PD-L1, MSI-H/dMMR) in these tumors. We performed genomic and transcriptomic analysis to confirm associations of mutant RAS with immune infiltration of the TME conducive to metastasis vs. potential response to immunotherapies. Methods: A total of 7,801 CRC were analyzed using next-generation sequencing on DNA (NextSeq, 592 Genes and WES, NovaSEQ), RNA (NovaSeq, whole transcriptome equencing) and IHC (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by FA, IHC and NGS. TMB-H was based on a cut-off of > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was <0.05. Results: Mutant KRAS was seen in 48% of mCRC tumors; NRAS in 3.7%, HRAS in 0.1%. The distribution was similar in patients < or >= than 50 yrs. In MSS tumors, there was a significantly higher neutrophil infiltration in KRAS MT (median cell fraction 6.6% vs. 5.9%) and NRAS MT (6.9%) overall and also when individual codons were studied. B cells, M2 macrophages, CD8+ T cells, dendritic cells and fibroblasts were lower in KRAS mutant tumors; B cells and M1 macrophages are lower in NRAS (q<0.05). dMMR/MSI-H was significantly more prevalent in RAS WT (9.1%) than in KRAS (2.9%) or NRAS MT (1.8%) tumors, and highest in HRAS MT tumors (60%, q<0.05).TMB-H was more prevalent in RAS WT (11%) than KRAS (5.8%) or NRAS (5.1%) MT, and highest in HRAS MT tumors (70%, all q<0.05). In MSS tumors, KRAS MT tumors showed more TMB-H than WT (3.1% vs. 2.1%, q<0.05), especially in KRAS non 12/13/61 mutations (5.5%, vs. 2.1%, q<0.05) and G12C (4.4%, p<0.05). PD-L1 expression was studied: in MSS tumors, KRAS-G12D (10.4%) and G13 MT (11.8%) showed higher mutation rates than RAS WT tumors (q<0.05). Conclusions: KRAS & NRAS mutations are associated with increased neutrophil abundance, with codon specific differences, while HRAS shows no difference. Overall CD8+ T cells and B cells are less abundant in KRAS & NRAS mutants; substantial variability was seen amongst different protein changes. RAS mutations were more prevalent overall than generally reported, but did not vary by age. These results demonstrate significant differences in the TME of RAS mutant CRC that identify variable susceptibilities to immuno-oncologic agents, and provide further detailed characterization of heterogeneity between RAS variants, at the molecular as well as immunogenic levels.

scholarly journals Correlations Between Tumor Mutation Burden and Immunocyte Infiltration and Their Prognostic Value in Colon Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhangjian Zhou ◽  
Xin Xie ◽  
Xuan Wang ◽  
Xin Zhang ◽  
Wenxin Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Prediction Model ◽  
Somatic Mutation ◽  
Gene Set Enrichment ◽  
Tumor Mutation Burden ◽  
Immune Infiltration ◽  
Mutation Burden ◽  
Prognostic Prediction ◽  
Checkpoint Genes

BackgroundColon cancer has a huge incidence and mortality worldwide every year. Immunotherapy could be a new therapeutic option for patients with advanced colon cancer. Tumor mutation burden (TMB) and immune infiltration are considered critical in immunotherapy but their characteristics in colon cancer are still controversial.MethodsThe somatic mutation, transcriptome, and clinical data of patients with colon cancer were obtained from the TCGA database. Patients were divided into low or high TMB groups using the median TMB value. Somatic mutation landscape, differentially expressed genes, and immune-related hub genes, Gene Ontology and KEGG, gene set enrichment, and immune infiltration analyses were investigated between the two TMB groups. Univariate and multivariate Cox analyses were utilized to construct a prognostic gene signature. The differences in immune infiltration, and the expression of HLA-related genes and checkpoint genes were investigated between the two immunity groups based on single sample gene set enrichment analysis. Finally, a nomogram of the prognostic prediction model integrating TMB, immune infiltration, and clinical parameters was established. Calibration plots and receiver operating characteristic curves (ROC) were drawn, and the C-index was calculated to assess the predictive ability.ResultsMissense mutations and single nucleotide polymorphisms were the major variant characteristics in colon cancer. The TMB level showed significant differences in N stage, M stage, pathological stage, and immune infiltration. CD8+ T cells, activated memory CD4+ T cells, activated NK cells, and M1 macrophages infiltrated more in the high-TMB group. The antigen processing and presentation signaling pathway was enriched in the high-TMB group. Two immune related genes (CHGB and SCT) were identified to be correlated with colon cancer survival (HR = 1.39, P = 0.01; HR = 1.26, P = 0.02, respectively). Notably, the expression of SCT was identified as a risk factor in the immune risk model, in which high risk patients showed poorer survival (P = 0.04). High immunity status exhibited significant correlations with immune response pathways, HLA-related genes, and immune checkpoint genes. Finally, including nine factors, our nomogram prediction model showed better calibration (C-index = 0.764) and had an AUC of 0.737.ConclusionIn this study, we investigated the patterns and prognostic roles of TMB and immune infiltration in colon cancer, which provided new insights into the tumor microenvironment and immunotherapies and the development of a novel nomogram prognostic prediction model for patients with colon cancer.

scholarly journals Tumor Mutation Burden-Associated LINC00638/miR-4732-3p/ULBP1 Axis Promotes Immune Escape via PD-L1 in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Feng Qi ◽  
Xiaojing Du ◽  
Zhiying Zhao ◽  
Ding Zhang ◽  
Mengli Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Prognostic Model ◽  
Immune Escape ◽  
Prognostic Score ◽  
Machine Learning Algorithms ◽  
Luciferase Reporter ◽  
Tumor Mutation Burden ◽  
Immune Infiltration ◽  
Cerna Network ◽  
Mutation Burden

Tumor mutation burden (TMB) is associated with immune infiltration, while its underlying mechanism in hepatocellular carcinoma (HCC) remains unclear. A long noncoding RNA (lncRNA)-related competitive endogenous RNA (ceRNA) network can regulate various tumor behaviors, and research about its correlation with TMB and immune infiltration is warranted. Data were downloaded from TCGA and ArrayExpress databases. Cox analysis and machine learning algorithms were employed to establish a lncRNA-based prognostic model for HCC. We then developed a nomogram model to predict overall survival and odds of death for HCC patients. The association of this prognostic model with TMB and immune infiltration was also analyzed. In addition, a ceRNA network was constructed by using DIANA-LncBasev2 and the starBase database and verified by luciferase reporter and colocalization analysis. Multiplex immunofluorescence was applied to determine the correlation between ULBP1 and PD-L1. An eight-lncRNA (SLC25A30-AS1, HPN-AS1, LINC00607, USP2-AS1, HCG20, LINC00638, MKLN1-AS and LINC00652) prognostic score model was constructed for HCC, which was highly associated with TMB and immune infiltration. Next, we constructed a ceRNA network, LINC00638/miR-4732-3p/ULBP1, that may be responsible for NK cell infiltration in HCC with high TMB. However, patients with high ULBP1 possessed a poorer prognosis. Using multiplex immunofluorescence, we found a significant correlation between ULBP1 and PD-L1 in HCC, and patients with high ULBP1 and PD-L1 had the worst prognosis. In brief, the eight-lncRNA model is a reliable tool to predict the prognosis of HCC patients. The LINC00638/miR-4732-3p/ULBP1 axis may regulate immune escape via PD-L1 in HCC with high TMB.

scholarly journals Identification of NTRK3 as a potential prognostic biomarker associated with tumor mutation burden and immune infiltration in bladder cancer

2021 ◽  
Author(s):  
Zhao Zhang ◽  
Yongbo Yu ◽  
Pengfei Zhang ◽  
Guofeng Ma ◽  
Mingxin Zhang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Ribosome Biogenesis ◽  
Prognostic Biomarker ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
High Morbidity ◽  
Tumor Mutation Burden ◽  
Immune Infiltration ◽  
Mutation Burden ◽  
Key Genes

Abstract Background Bladder cancer (BLCA) is a common malignant tumor of urinary system with high morbidity and mortality. In recent years, immunotherapy plays a significant role in the treatment of BLCA. Tumor mutation burden (TMB) has been reported to be a powerful biomarker to predict tumor prognosis and efficacy of immunotherapy. Our study aimed to explore the relationship between TMB, prognosis and immune infiltration to excavate the key genes in BLCA. Methods Clinical information, somatic mutation and gene expression data of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA) database. According to the calculated TMB scores, patients were divided into high and low TMB groups. Gene Set Enrichment Analysis (GSEA) was performed to screen significantly enriched pathways. Differentially expressed genes (DEGs) between the two groups were identified. Univariate cox analysis and Kaplan-Meier survival analysis were applied for screening key genes. Immune infiltration was performed for TMB groups and NTRK3. Results Higher TMB scores were related with poor survival in BLCA. After filtering, 36 DEGs were identified. NTRK3 had the highest hazard ratio and significant prognostic value. Co-expressed genes of NTRK3 were mainly involved in several pathways, including DNA replication, basal transcription factors, complement and coagulation cascades, and ribosome biogenesis in eukaryotes. There was a significant correlation among TMB scores, NTRK3 expression and immune infiltration. Conclusions Our results suggest that NTRK3 is a TMB-related prognostic biomarker, which lays the foundation for further research on the immunomodulatory effect of NTRK3 in BLCA.

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