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.

scholarly journals Tumor mutation burden in connection with immune-related survival in uterine corpus endometrial carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ling Zhao ◽  
Xueshu Fu ◽  
Xiling Han ◽  
Yanjun Yu ◽  
Yaping Ye ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Prognostic Models ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Tumor Mutation Burden ◽  
Immune Genes ◽  
Mutation Burden

Abstract Background UCEC is the most common gynecological malignancy in many countries, and its mechanism of occurrence and development is related to tumor mutation burden (TMB) and immune cell infiltration. Therefore, it is necessary to systematically explore the TMB-related gene profile in immune cells to improve the prognosis of UCEC. Methods We integrated TMB-related genes with basic clinical information of UCEC patients based on TCGA dataset. Differentially expressed genes (DEGs) were selected through differential expression screening, PPI, and enrichment analysis. Additionally, we analyzed the components of immune cell infiltration of the DEGs to obtain the differential immunity-related genes. A single factor and multifactor Cox regression analyses were conducted to establish new prognostic indicators of OS and DFS based on TMB-related immune genes. To further study the correlation between survival and immune cell infiltration, a Cox model based on these immune infiltration compositions was built. Using the clinical variables, we established nomograms for OS and DFS. Results 393 DEGs were significantly associated with clinical outcomes and the immune component in patients with UCEC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) pathway and protein-protein interaction network (PPI) analyses revealed the role of these genes and information on related pathways. Then, two prognostic models were established based on the differential immune genes for OS (GFAP and MX2) and DFS (MX2, GFAP, IGHM, FGF20, and TRAV21). In DFS, the differential immune genes were related to CD4+ T cell, CD8+ T cell, macrophage, and neutrophil (all P < 0.05). B cell and CD8+ T cell were independent prognostic factors from among the immune cell elements in UCEC. Finally, the risk scores of these models were combined with the clinical elements-based nomogram models, and the AUC values were all over 0.7. Conclusions Our results identified several clinically significant differential immune genes and established relevant prognostic models, providing a basis for the molecular analysis of TMB and immune cells in UCEC, and identified potential prognostic and immune-related genes for UCEC. We added clinical related conditions for further analysis to confirm the identity of the genes and clinical elements-based models.

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

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 The landscape of T cell infiltration in human cancer and its association with antigen presenting gene expression

2015 ◽  
Author(s):  
Yasin Senbabaoglu ◽  
Andrew G Winer ◽  
Ron S Gejman ◽  
Ming Liu ◽  
Augustin Luna ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Immune Cell ◽  
T Cell Subsets ◽  
Cell Infiltration ◽  
Th2 Cells ◽  
Immune Infiltration ◽  
T Cell Infiltration ◽  
Mutation Burden ◽  
Antigen Presenting

Infiltrating T cells in the tumor microenvironment have crucial roles in the competing processes of pro-tumor and anti-tumor immune response. However, the infiltration level of distinct T cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery (APM) genes, remain poorly characterized across human cancers. Here, we define a novel mRNA-based T cell infiltration score (TIS) and profile infiltration levels in 19 tumor types. We find that clear cell renal cell carcinoma (ccRCC) is the highest for TIS and among the highest for the correlation between TIS and APM expression, despite a modest mutation burden. This finding is contrary to the expectation that immune infiltration and mutation burden are linked. To further characterize the immune infiltration in ccRCC, we use RNA-seq data to computationally infer the infiltration levels of 24 immune cell types in a discovery cohort of 415 ccRCC patients and validate our findings in an independent cohort of 101 ccRCC patients. We find three clusters of tumors that are primarily separated by levels of T cell infiltration and APM gene expression. In ccRCC, the levels of Th17 cells and the ratio of CD8+ T/Treg levels are associated with improved survival whereas the levels of Th2 cells and Tregs are associated with negative clinical outcome. Our analysis illustrates the utility of computational immune cell decomposition for solid tumors, and the potential of this method to guide clinical decision-making.

scholarly journals Tumor mutation burden testing: a survey of the International Quality Network for Pathology (IQN Path)

2021 ◽  
Author(s):  
Francesca Fenizia ◽  
Nicola Wolstenholme ◽  
Jennifer A. Fairley ◽  
Etienne Rouleau ◽  
Melanie H. Cheetham ◽  
...  
Keyword(s):  
Current Practice ◽  
Checkpoint Inhibitors ◽  
Testing Methods ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Tumor Mutation Burden ◽  
Formalin Fixed Paraffin ◽  
Mutation Burden ◽  
Formalin Fixed Paraffin Embedded ◽  
Formalin Fixed

AbstractWhile tumour mutation burden (TMB) is emerging as a possible biomarker for immune-checkpoint inhibitors (ICI), methods for testing have not been standardised as yet. In April 2019, the International Quality Network for Pathology (IQN Path) launched a survey to assess the current practice of TMB testing. Of the 127 laboratories that replied, 69 (54.3%) had already introduced TMB analysis for research purposes and/or clinical applications. Fifty laboratories (72.5%) used targeted sequencing, although a number of different panels were employed. Most laboratories tested formalin-fixed paraffin-embedded material (94.2%), while 18/69 (26%) tested also cell-free DNA. Fifty-five laboratories used both single nucleotide variants and indels for TMB calculation; 20 centers included only non-synonymous variants. In conclusion, the data from this survey indicate that multiple global laboratories were capable of rapidly introducing routine clinical TMB testing. However, the variability of testing methods raises concerns about the reproducibility of results among centers.

scholarly journals m6A Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pancreatic Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengyu Sun ◽  
Meng Xie ◽  
Tongyue Zhang ◽  
Yijun Wang ◽  
Wenjie Huang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Clustering Algorithm ◽  
Immune Cell ◽  
Biological Processes ◽  
Consensus Clustering ◽  
Tumor Mutation Burden ◽  
Immune Infiltration ◽  
Signature Genes ◽  
Mutation Burden

Recent studies have shown that RNA N6-methyladenosine (m6A) modification plays an important part in tumorigenesis and immune-related biological processes. However, the comprehensive landscape of immune cell infiltration characteristics in the tumor microenvironment (TME) mediated by m6A methylation modification in pancreatic cancer has not yet been elucidated. Based on consensus clustering algorithm, we identified two m6A modification subtypes and then determined two m6A-related gene subtypes among 434 pancreatic cancer samples. The TME characteristics of the identified gene subtypes were highly consistent with the immune-hot phenotype and the immune-cold phenotype respectively. According to the m6A score extracted from the m6A-related signature genes, patients can be divided into high and low m6A score groups. The low score group displayed a better prognosis and relatively strong immune infiltration. Further analysis showed that low m6A score correlated with lower tumor mutation burden and PD-L1 expression, and indicated a better response to immunotherapy. In general, m6A methylation modification is closely related to the diversity and complexity of immune infiltration in TME. Evaluating the m6A modification pattern and immune infiltration characteristics of individual tumors can help deepen our understanding of the tumor microenvironment landscape and promote a more effective clinical practice of immunotherapy.

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 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.

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