scholarly journals Development of Prognostic Model Based on Five-gene Related to Tumor Mutation Burden in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Zhou Shujun ◽  
Qingling Li ◽  
Bin Yu ◽  
Qifa Ye ◽  
Yanfeng Wang
Keyword(s):  
The Cancer Genome Atlas ◽  
Missense Mutations ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Prognosis Model ◽  
Cancer Genome Atlas ◽  
Matrix Organization ◽  
The Individual ◽  
Therapeutic Decision Making ◽  
High Level

Abstract BackgroundHepatocellular carcinoma (HCC) , the incidence rate ranks sixth and regards as the second leading cause of cancer-related death in the world. Tumor mutation burden (TMB) , a novel biomarker featured with microsatellite instability, has been thought to be closely related to tumor microenvironment and immunotherapy.MethodsIn this study, the 357 HCC samples were download from The Cancer Genome Atlas (TCGA) and analyzed.ResultsSingle nucleotide polymorphism (SNP) and C > T variation had the most missense mutations, and we also observed the higher mutation frequency in TP53, TTN, CTNNB1. With an optimal cut-off value of 4.61, the high level of TMB presented a worse prognosis. Functional analysis of the differentially expressed genes (DEGs) showed they were enriched in the pathway of the formation of extracellular matrix organization and sulfur compound metabolic. A 5-gene-based (including SFRP4, IL7R, FBLN2, COLEC10 and CHGA) model has been constructed to explore the independent prognosis capacity of each HCC patient.ConclusionsThe establishment of 5-gene-based prognosis model functions well in predicting the median of 1- , 3- and 5-year outcome of the individual patient and which will be beneficial for pre-clinical diagnosis and therapeutic decision-making.

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 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.

scholarly journals Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Accuracy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Oncogenic Pathways ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

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 Pan-cancer analysis of SETD2 mutation and its association with the efficacy of immunotherapy

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Mingdong Lu ◽  
Bin Zhao ◽  
Mengshan Liu ◽  
Le Wu ◽  
Yingying Li ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
The Cancer Genome Atlas ◽  
Genomic Integrity ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Pan Cancer ◽  
Genome Atlas

AbstractHistone methyltransferase SETD2 plays a critical role in maintaining genomic integrity and stability. Here, we investigated the characteristics of SETD2 somatic mutation in the cancer genome atlas pan-cancer cohort. Our data revealed that, compared with SETD2 nonmutant patients, SETD2 mutant patients had higher tumor mutation burden and microsatellite instability. In addition, the transcriptions of most genes related to immune activities were upregulated in patients with SETD2 mutant tumors. Further examination of cancer patients treated with immune checkpoint inhibitors suggested SETD2 mutation was associated with favorable clinical outcomes. These results have implication for the personalization of cancer immunotherapy.

scholarly journals Characterization of m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration in Ovarian Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Yihong Luo ◽  
Xiang Sun ◽  
Jian Xiong
Keyword(s):  
Ovarian Cancer ◽  
Principal Component ◽  
Notch Signaling Pathway ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Introduction: Studies have demonstrated the epigenetic regulation of immune responses in various cancers. However, little is known about the RNA N6-methyladenosine (m6A) modification patterns of the microenvironment (TME) cell infiltration in ovarian cancer (OC).Methods: We evaluated the correlation between m6A modification patterns and TME cell infiltration based on 459 OC samples from the Cancer Genome Atlas and Gene-Expression Omnibus database. We constructed an m6Ascore system to quantify m6A modification patterns using principal component analysis.Results: Based on unsupervised clustering, three m6A modification patterns were identified. Gene set variation analysis showed that the antigen presentation signal pathway, the NOTCH signaling pathway, and the metabolism-related pathway differed significantly across m6A modificaiton patterns. The m6Ascore is closely correlated with TME cell infiltration. OC patients with lower m6Ascores had worse outcomes. There was better risk stratification with combined m6Ascore and tumor mutation burden. The responses to immune checkpoint inhibitor treatment significantly differed between high and low m6Ascore groups.Conclusion: M6A modification plays an essential role in TME cell infiltration in OC. Evaluating the m6A modification patterns in OC patients could enhance our understanding of TME infiltration characterization and guide immunotherapy strategies.

scholarly journals Imprints of tumor mutation burden on chromosomes and relation to cancer risk in humans: A pan-cancer analysis

2020 ◽  
Author(s):  
Xin Li ◽  
D. Thirumalai
Keyword(s):  
Cancer Risk ◽  
Somatic Mutations ◽  
Latency Period ◽  
Mean Value ◽  
Small Chromosome ◽  
The Cancer Genome Atlas ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
History Of ◽  
Cancer Genome Atlas

Cancers, resulting in uncontrolled cell proliferation, are driven by accumulation of somatic mutations. Genome-wide sequencing has produced a catalogue of millions of somatic mutations, which contain the evolutionary history of the cancers. However, the connection between the mutation accumulation and disease development and risks is poorly understood. Here, we analyzed more than 1,200,000 mutations from 5,000 cancer patients and revealed two novel signatures for 16 cancer types in The Cancer Genome Atlas (TCGA) database. A strong correlation between Tumor Mutation Burden (TMB) and the Patient Age at Diagnosis (PAD) is observed for cancers with low TMB (mean value less than 3 mutations per million base pairs) but is absent in cancers with high TMB. Surprisingly, the differences in cancer risk between the sexes are also mainly driven by the disparity in mutation burden. The TMB variations, imprinted at the chromosome level, also reflect accumulation of mutation clusters within small chromosome segments in high TMB cancers. A model, relating mutation rates to PAD and latency period for cancer detection, explains the key findings.

scholarly journals Role of Tumor Mutation Burden-related Signatures in the Prognosis and Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Accuracy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Oncogenic Pathways ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. Nonetheless, whether high TMB could predict the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC), a classic “cold” tumor, remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC.Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMSIhigh was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits.Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

scholarly journals PEG3 mutation is associated with elevated tumor mutation burden and poor prognosis in breast cancer

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Min Zhang ◽  
Jin Zhang
Keyword(s):  
Breast Cancer ◽  
The Cancer Genome Atlas ◽  
Confounding Factors ◽  
Breast Cancer Patients ◽  
Wild Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Brca1 Brca2 ◽  
Common Malignancy

Abstract Background: Breast cancer is the second most common malignancy in women and considered as a severe health burden. PEG3 mutations have been observed in several cancers. However, the associations of PEG3 mutation with tumor mutation burden (TMB) and prognosis in breast cancer have not been investigated. Methods: In our study, the somatic mutation data of 986 breast cancer patients from The Cancer Genome Atlas (TCGA) were analyzed. Results: It showed that PEG3 had a relatively high mutation rate (2%). After calculated the TMB in PEG3 mutant and PEG3 wild-type groups, we found the TMB value was significantly higher in PEG3 mutant samples than that in PEG3 wild-type samples (P = 5.6e-07), which was independent of the confounding factors including age, stage, mutations of BRCA1, BRCA2 and POLE (odd ratio, 0.45; 95% CI, 0.20–0.98; P=0.044). Survival analysis revealed that PEG3 mutant samples had inferior survival outcome compared with the PEG3 wild-type samples after adjusted for the confounding factors above (hazard ratio, 0.27; 95% CI: 0.12–0.57; P<0.001). Conclusion: These results illustrated that PEG3 mutation was associated with high TMB and inferior prognosis, suggesting PEG3 mutation might play a guiding role in prognosis prediction and immunotherapy selection in breast cancer.

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