scholarly journals FAT3 Mutation Is Associated With Tumor Mutation Burden and Poor Prognosis in Esophageal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zixin Guo ◽  
Xin Yan ◽  
Congkuan Song ◽  
Qingwen Wang ◽  
Yujin Wang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Prognostic Marker ◽  
Somatic Mutation ◽  
Poor Prognosis ◽  
Potential Mechanism ◽  
Wild Type ◽  
Mutant Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Mutation Type

ObjectiveTo explore the mutated genes in esophageal cancer (ESCA), and evaluate its relationship with tumor mutation burden (TMB) and prognosis of ESCA, and analyze the advantages of FAT3 as a potential prognostic marker in ESCA.MethodsThe somatic mutation landscape was analyzed according to ESCA samples from the TCGA and ICGC database. The differences of TMB between mutant type and wild type of frequently mutated genes were compared by Mann-Whitney U test. The association of gene mutations with prognosis was analyzed by Kaplan-Meier method. The relative abundance of 22 tumor-infiltrating lymphocyte subsets in ESCA was calculated by CIBERSORT algorithm.ResultsFAT3 was a high frequency mutation in both TCGA and ICGC samples from the somatic mutation landscape. Then, the mutation type of FAT3 had significantly higher TMB in patients with ESCA compared the wild type (P<0.05). Meanwhile, the prognosis of FAT3 mutation type was significantly worse in patients with ESCA(P<0.05), and the FAT3 mutation status might be an independent factor for prognosis of patients with ESCA (HR: 1.262–5.922, P=0.011). The GSEA analysis revealed the potential mechanism of FAT3 mutation on the occurrence and development of ESCA. Finally, naive B cells were significantly enriched in FAT3 mutation samples of the ESCA microenvironment (P<0.05).ConclusionsFAT3 mutation is related to TMB and poor prognosis in ESCA. FAT3 mutation may be a prognostic marker of ESCA, and reveal the potential mechanism of FAT3 mutation on ESCA.

RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16528-e16528
Author(s):  
Liping Li ◽  
Mengmei Yang ◽  
Mengli Huang
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Negative Regulator ◽  
Wilcoxon Test ◽  
Wild Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
The Impact

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16650-e16650
Author(s):  
Lingling Guo ◽  
Xiaoxia Kou ◽  
Panpan Song ◽  
Xiaoyu Zhang ◽  
Hongjuan Zhang ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Poor Prognosis ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Biliary Tract Carcinoma ◽  
Rank Test ◽  
Braf Mutations ◽  
Tumor Mutation Burden ◽  
Synonymous Mutations ◽  
Mutation Burden

e16650 Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( > 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.

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.

Papillary thyroid carcinoma with a high tumor mutation burden has a poor prognosis

2020 ◽  
Vol 89 ◽  
pp. 107090
Author(s):  
Zhenyu Xie ◽  
Xin Li ◽  
Yu Lun ◽  
Yuzhen He ◽  
Song Wu ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Poor Prognosis ◽  
Papillary Thyroid ◽  
Tumor Mutation Burden ◽  
Mutation Burden

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 ­ Characterization of the Immune Infiltration Landscape and Identification of Prognostic Biomarkers for Esophageal Cancer

2021 ◽  
Author(s):  
Yuanmei Chen ◽  
Xinyi Huang ◽  
Haiyan Peng ◽  
Guibin Weng ◽  
Zhengrong Huang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Esophageal Cancer ◽  
Prognostic Model ◽  
Cox Regression ◽  
Expression Profiles ◽  
Cancer Genome ◽  
Prognostic Models ◽  
Tumor Mutation Burden ◽  
Cox Regression Analysis ◽  
Mutation Burden

Abstract Background. Esophageal cancer (EC) is the 7th most common neoplasm and the 6th most common cause of cancer-related death worldwide. Immunotherapy is an effective treatment for EC patients. However, there are no dependable markers for predicting prognosis and immunotherapy responses in EC. Our study aims to explore prognostic models and markers in EC as well as predictors for immunotherapy. Methods. The expression profiles of EC were obtained from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC) databases. Cox regression analysis was performed to construct a prognostic model. Overall survival and receiver operating characteristic curve analyses were applied to verify the accuracy of the model. The CIBERSORT algorithm was conducted to quantify the infiltration of different immune cells, and EC was grouped into three immune cell infiltration (ICI) clusters. PD-1 and PD-L1 expressions were compared between the ICI clusters. Overall survival analysis between ICI score and tumor mutation burden was conducted. The immunotherapy response of patients in different ICI score clusters was also compared. The copy number variations, somatic mutations, and single nucleotide polymorphisms were analyzed. Enrichment analyses were also performed. Results. A prognostic model was successfully constructed. Three ICI clusters were identified, and the clusters with high immune and stromal scores tended to have more immune-activated phenotypes and higher expressions of PD-1 and PDL1. The ICI score may be used as a predictor independent of tumor mutation burden. Patients with higher ICI score tended to have better immunotherapeutic responses than those with lower scores. Enrichment analyses showed that the differentially expressed genes were mostly enriched in microvillus and the KRAS and IL6/JAK/STAT3 pathways. The top eight genes with the highest mutation frequencies in EC were identified and all related to the prognosis of EC patients. Conclusions. Our study established an effective prognostic model and identified markers for predicting the prognosis and immunotherapy response of EC patients.

scholarly journals CDC20 is a Potential Prognostic and Immunological Biomarker in Pan-Cancer

2021 ◽  
Author(s):  
Chen Tao ◽  
Hu Bing ◽  
Zhan Xiangpeng ◽  
Liu Xiaoqiang ◽  
Deng Wen ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Vital Role ◽  
Pathological Stage ◽  
Cycle Progression ◽  
Tumor Mutation Burden ◽  
Normal Tissues ◽  
Mutation Burden ◽  
Immune Related Genes ◽  
Pan Cancer

Abstract BackgroundCDC20(cell division cycle 20 homologue) plays a vital role in the cell cycle progression through targeting key substrates for destruction. Current studies have shown that CDC20 functions as an oncogene in various cancers. However, the potential correlations of CDC20 with prognosis and immune infiltrates in different cancers remain unclear.ResultCDC20 expression was higher in most cancers, compared with normal tissues, and the high expression of CDC20 was correlated with poor prognosis and a higher pathological stage. Furthermore, there were significant correlations between CDC20 dysregulation with tumor mutation burden(TMB), microsatellite instability(MSI), tumor microenvironment and tumor- and immune-related genes.ConclusionCDC20 may be used as a potential prognostic and immunotherapeuticbiomarker which affects tumor progression.

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