scholarly journals Comprehensive Analysis of Genomic Mutation Signature and Tumor Mutation Burden for Prognosis of Intrahepatic Cholangiocarcinoma

2020 ◽  
Author(s):  
Rui Zhang ◽  
Qi Li ◽  
Jialu Fu ◽  
Zhechuan Jin ◽  
Jingbo Su ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Intrahepatic Cholangiocarcinoma ◽  
Cox Regression ◽  
Tnm Stage ◽  
Gene Set Enrichment Analysis ◽  
Tumor Mutation Burden ◽  
Kaplan Meier ◽  
Mutation Burden ◽  
Genomic Mutation

Abstract Background: The intrahepatic cholangiocarcinoma (iCCA) is highly lethal malignancy of biliary tract cancer. Analysis of somatic mutational profiling could help to reveal new prognostic markers and actionable targets for treatment. We aim to explore the impact of genomic mutation signature and tumor mutation burden (TMB) on prognosis of iCCA patients. Methods: The whole-exome sequencing and corresponding clinical data were collected from ICGC portal and cBioPortal database to detect the mutation prognostic genes and TMB values. To identify the hub prognostic mutant signature, Cox regression and Lasso feature selection were conducted. We built a mutation related signature (MRS) through multivariate Cox regression. The predictive performance of MRS and TMB were assessed using Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC). We performed a functional enrichment pathway analysis with gene set enrichment analysis (GSEA) for mutated genes were conducted. Moreover, on the base of MRS, TMB and TNM stage, a nomogram was constructed to visualize the prognosis of iCCA patients.Results: The mutation landscape illustrated the distributions of mutation frequencies and types on iCCA, and revealed a list of most frequent mutation genes (such as Tp53, KRAS, ARID1A, IDH1). We obtain a 6- gene signature using the Lasso and Cox method. The AUC of MRS in 1, 3, 5-year OS prediction were 0.759, 0.732, 0.728, respectively. Moreover, Kaplan-Meier analysis showed a significant difference on the prognosis of iCCA with high and low MRS score (P <0.001). Interestingly, GSEA was utilized to show several signaling pathways including MAPK signaling pathway, PI3K-AKT signaling pathway and proteoglycans in cancer. On the other hand, survival analysis indicated that TMB was significantly associated with prognosis. And GSEA indicated that samples with high MRS or TMB upregulated signaling pathways involved in tumor signaling and immune system. At last, we constructed a predictive nomogram (included MRS, TMB and TNM stage) with satisfactory performance in survival prediction. Conclusions: The mutation genes signature and TMB were associated with prognosis in patients with iCCA. Our study provides a valuable prognostic predictor for further uncovering molecular pathogenesis in iCCA.

scholarly journals Comprehensive analysis of genomic mutation signature and tumor mutation burden for prognosis of intrahepatic cholangiocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Zhang ◽  
Qi Li ◽  
Jialu Fu ◽  
Zhechuan Jin ◽  
Jingbo Su ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Cox Regression ◽  
Tnm Stage ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Tumor Mutation Burden ◽  
Kaplan Meier ◽  
Mutation Burden ◽  
Significant Difference ◽  
Genomic Mutation

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy of the biliary tract. Analysis of somatic mutational profiling can reveal new prognostic markers and actionable treatment targets. In this study, we explored the utility of genomic mutation signature and tumor mutation burden (TMB) in predicting prognosis in iCCA patients. Methods Whole-exome sequencing and corresponding clinical data were collected from the ICGC portal and cBioPortal database to detect the prognostic mutated genes and determine TMB values. To identify the hub prognostic mutant signature, we used Cox regression and Lasso feature selection. Mutation-related signature (MRS) was constructed using multivariate Cox regression. The predictive performances of MRS and TMB were assessed using Kaplan–Meier (KM) analysis and receiver operating characteristic (ROC). We performed a functional enrichment pathway analysis using gene set enrichment analysis (GSEA) for mutated genes. Based on the MRS, TMB, and the TNM stage, a nomogram was constructed to visualize prognosis in iCCA patients. Results The mutation landscape illustrated distributions of mutation frequencies and types in iCCA, and generated a list of most frequently mutated genes (such as Tp53, KRAS, ARID1A, and IDH1). Thirty-two mutated genes associated with overall survival (OS) were identified in iCCA patients. We obtained a six-gene signature using the Lasso and Cox method. AUCs for the MRS in the prediction of 1-, 3-, and 5-year OS were 0.759, 0.732, and 0.728, respectively. Kaplan–Meier analysis showed a significant difference in prognosis for patients with iCCA having a high and low MRS score (P < 0.001). GSEA was used to show that several signaling pathways, including MAPK, PI3K-AKT, and proteoglycan, were involved in cancer. Conversely, survival analysis indicated that TMB was significantly associated with prognosis. GSEA indicated that samples with high MRS or TMB also showed an upregulated expression of pathways involved in tumor signaling and the immune response. Finally, the predictive nomogram (that included MRS, TMB, and the TNM stage) demonstrated satisfactory performance in predicting survival in patients with iCCA. Conclusions Mutation-related signature and TMB were associated with prognosis in patients with iCCA. Our study provides a valuable prognostic predictor for determining outcomes in patients with iCCA.

scholarly journals INHBB Is a Novel Prognostic Biomarker Associated with Cancer-Promoting Pathways in Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jinpeng Yuan ◽  
Aosi Xie ◽  
Qiangjian Cao ◽  
Xinxin Li ◽  
Juntian Chen
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction

Background. Inhibin subunit beta B (INHBB) is a protein-coding gene that participated in the synthesis of the transforming growth factor-β (TGF-β) family members. The study is aimed at exploring the clinical significance of INHBB in patients with colorectal cancer (CRC) by bioinformatics analysis. Methods. Real-time PCR and analyses of Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases were utilized to evaluate the INHBB gene transcription level of colorectal cancer (CRC) tissue. We evaluated the INHBB methylation level and the relationship between expression and methylation levels of CpG islands in CRC tissue. The corresponding clinical data were obtained to further explore the association of INHBB with clinical and survival features. In addition, Gene Set Enrichment Analysis (GSEA) was performed to explore the gene ontology and signaling pathways of INHBB involved. Results. INHBB expression was elevated in CRC tissue. Although the promoter of INHBB was hypermethylated in CRC, methylation did not ultimately correlate with the expression of INHBB. Overexpression of INHBB was significantly and positively associated with invasion depth, distant metastasis, and TNM stage. Cox regression analyses and Kaplan-Meier survival analysis indicated that high expression of INHBB was correlated with worse overall survival (OS) and disease-free survival (DFS). GSEA showed that INHBB was closely correlated with 5 cancer-promoting signaling pathways including the Hedgehog signaling pathway, ECM receptor interaction, TGF-β signaling pathway, focal adhesion, and pathway in cancer. INHBB expression significantly promoted macrophage infiltration and inhibited memory T cell, mast cell, and dendritic cell infiltration. INHBB expression was positively correlated with stromal and immune scores of CRC samples. Conclusion. INHBB might be a potential prognostic biomarker and a novel therapeutic target for CRC.

scholarly journals Construction and Evaluation of a Tumor Mutation Burden-Related Prognostic Signature for Thyroid Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Haodong Lu ◽  
Qian Liu ◽  
Qing Chang ◽  
Jinghai Du ◽  
Chunying Zhang ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Clinicopathological Features ◽  
Gene Set Enrichment Analysis ◽  
Prognostic Signature ◽  
Tumor Mutation Burden ◽  
Cox Regression Analysis ◽  
Survival Status ◽  
Mutation Burden

Thyroid carcinoma is a type of prevalent cancer. Its prognostic evaluation depends on clinicopathological features. However, such conventional methods are deficient. Based on mRNA, single nucleotide variants (SNV), and clinical information of thyroid carcinoma from The Cancer Genome Atlas (TCGA) database, this study statistically analyzed mutational signature of patients with this disease. Missense mutation and SNV are the most common variant classification and variant type, respectively. Next, tumor mutation burden (TMB) of sample was calculated. Survival status of high/low TMB groups was analyzed, as well as the relationship between TMB and clinicopathological features. Results revealed that patients with high TMB had poor survival status, and TMB was related to several clinicopathological features. Through analysis on DEGs in high/low TMB groups, 381 DEGs were obtained. They were found to be mainly enriched in muscle tissue development through enrichment analysis. Then, through Cox regression analysis, a 5-gene prognostic signature was established, which was then evaluated through survival curves and receiver operation characteristic (ROC) curves. The result showed that the signature was able to effectively predict patient’s prognosis and to serve as an independent prognostic risk factor. Finally, through Gene Set Enrichment Analysis (GSEA) on high/low-risk groups, DEGs were found to be mainly enriched in signaling pathways related to DNA repair. Overall, based on the TCGA-THCA dataset, we constructed a 5-gene prognostic signature through a trail of bioinformatics analysis.

scholarly journals Low expression of CIP4 in predicting worse overall survival: A potential biomarker for laryngeal cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0253545
Author(s):  
Lucheng Fang ◽  
Licai Shi ◽  
Wen Wang ◽  
Xiu Wu ◽  
Tingting Hu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Laryngeal Cancer ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Gene Set Enrichment Analysis ◽  
Kaplan Meier ◽  
Potential Biomarker ◽  
The Relationship

Previous reports indicate that Cdc42-interacting protein-4 (CIP4) has previously been reported to plays an important role in the progression of various cancers. However, its correlation with laryngeal cancer (LC) remains unreported. Data from TCGA and GEO databases were used to evaluate the role of CIP4 in LC. Based on GEO and TCGA datasets, we analyzed the differences in CIP4 expression between normal and tumor samples. The Wilcoxon signed-rank test was used to analyze the relationship between clinical features and CIP4. Cox regression and the Kaplan-Meier analyses were used to identify the clinical characteristics associated with the overall survival. Also, the GEPIA database was used to confirm the relationship between CIP4 and overall survival. Lastly, Gene Set Enrichment Analysis (GSEA) was performed based on the TCGA dataset. CIP4 expression in LC was significantly associated with gender and tumor stage (p-values<0.05). Similar to GEPIA validation, Kaplan-Meier survival analysis demonstrated that LC with CIP4-low exhibited a worse prognosis than that with CIP4-high. Univariate analysis revealed that CIP4-high significantly correlated with better overall survival (HR: 0.522, 95% CI: 0.293–0.830, P = 0.026). Besides, multivariate analysis revealed that CIP4 remained independently associated with the overall survival (HR: 0.61, 95% CI: 0.326–0.912, P = 0.012). GSEA showed that the p53, WNT signaling, TGF-β signaling pathways, etc. were enriched in a phenotype high CIP4 expression. In summary, the CIP4 gene is a potential prognostic molecular marker for patients diagnosed with laryngeal cancer. Moreover, the p53, WNT signaling, and TGF-β signaling pathways are potentially associated with CIP4 in LC.

scholarly journals The effect of NLRP3 on tumors based on pan-cancer research

2021 ◽  
Author(s):  
Desheng Tang ◽  
Wei Li ◽  
Zhengjie Xu ◽  
Suxiao Jiang ◽  
Kun Fang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Cox Regression ◽  
Tumor Mutation Burden ◽  
Cox Regression Analysis ◽  
Related Data ◽  
Immune Resistance ◽  
Kaplan Meier ◽  
Mutation Burden ◽  
The Relationship

Abstract NLRP3 is a multi-protein complex in cells, which can directly or indirectly affect the tumor microenvironment and participate in tumor growth, invasion and metastasis. Tumor and normal tissue gene sequencing was downloaded, clinical and mutation-related data was obtained from the TCGA website, and Kaplan-Meier and cox regression analysis was used to analyze the relationship between NLRP3 and overall survival (OS) as well as Hazard ratio (HR). The correlation between NLRP3 and tumor microenvironment score, immune cell invasion, and immune resistance indicators (tumor mutation burden and microsatellite instability) was performed. Finally, the function of NLRP3 in tumors was analyzed by GSEA.Inflammation is one of the important factors that cause cancer.

scholarly journals Overexpression of MATN3 predicts poor prognosis of gastric adenocarcinoma: based on TCGA database

2020 ◽  
Author(s):  
GuoLiang Zheng ◽  
Yan Zhao ◽  
Zhichao Zheng
Keyword(s):  
Signaling Pathway ◽  
Gastric Adenocarcinoma ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Mtor Signaling ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Rank Test ◽  
Mtor Signaling Pathway ◽  
Kaplan Meier

Abstract Background Matrilin-3 (MATN3) was previously reported to in the cartilage extracellular matrix and had a role in the development and homeostasis of cartilage and bone. We evaluated the role of MATN3 in gastric adenocarcinoma (GAC) using publicly available data from The Cancer Genome Atlas (TCGA). Methods The relationship between clinicapathologic features and MATN3 were analyzed with the Wilcoxon signed-rank test and logistic regression. Clinicopathologic variables associated with overall survival (OS) in TCGA patients using Cox regression and the Kaplan-Meier method. Gene Set Enrichment Analysis (GSEA) was performed using TCGA cohort. Results MATN3 overexpressed in GAC than that in normal tissues (p﹤0.05), and MATN3 overexpression was significantly associated with TNM stage (p= 0.012), and T stage (p﹤0.01). Kaplan-Meier survival analysis showed that GAC with MATN3 - high had a worse prognosis than that with MATN3- low (p﹤0.01). The univariate analysis revealed that MATN3- high correlated significantly with a poor OS (HR: 1.86; 95% confidence interval [CI]: 0.82- 2.01; p = 0.014). The multivariate analysis revealed that MATN3 remained independently associated with OS, with a HR of 2.68 (CI: 0.74- 2.13; p﹤0.01). GSEA showed that NOTCH, WNT, and MTOR signaling pathway were differentially enriched in MANT3 high expression phenotype. Conclusion Overexpression of MATN3 may be a potential prognostic biomarker of poor survival in gastric cancer, Moreover, NOTCH, WNT, and MTOR signaling pathway may be the key pathway regulated by MATN3 in GAC.

scholarly journals The overexpression of FKBP4 in patients with lung adenocarcinoma predicts poor prognosis and tumor progression

2021 ◽  
Author(s):  
Sha Tian ◽  
Shang qing Wang ◽  
Piao Zheng ◽  
Xu Zhu ◽  
Huan Han ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Clinicopathological Parameters ◽  
Poor Overall Survival ◽  
Kaplan Meier

Abstract Background: The FK506-binding protein 4 ( FKBP4 ), a tumor-related gene, plays a vital role in tumorigenesis and cancer progression. The study is aimed to clarify the effect of FKBP4 in lung adenocarcinoma (LUAD). Methods: Relying on The Cancer Genome Atlas (TCGA) cohort, the FKBP4 expression difference between LUAD tissues and non-tumor tissues was first detected, and verified with public tissue microarrays (TMAs), clinical LUAD specimen cohort and Gene Expression Omnibus (GEO) cohort. Then, logistic regression analysis and chi-square test were applied to detect the correlation between FKBP4 expression and clinicopathological parameters. Kaplan-Meier survival analysis and Cox regression model were utilized to evaluate the effect of FKBP4 expression on survival. Signaling pathways related to LUAD were obtained via employing Gene Set Enrichment Analysis (GSEA). Results: The FKBP4 expression level in LUAD samples was dramatically higher than that in non-tumor samples. High FKBP4 expression in LUAD is associated with gender, pathological stage, T classification, lymph node metastasis and distant metastasis. The Kaplan-Meier curve indicated a poor prognosis for LUAD patients with high FKBP4 expression. Multivariate analysis suggested that the high FKBP4 expression was a vital independent predictor of poor overall survival (OS). GSEA showed that a total of 15 signaling pathways were enriched in samples with high FKBP4 expression phenotype. Conclusions: FKBP4 may be an oncogene in LUAD, and is promised to become a prognostic indicator and therapeutic target for LUAD.

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.

Transmembrane p24 Trafficking Protein 2 Regulates Inflammation Through the TLR4/NF-κB Signaling Pathway in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Longhua Feng ◽  
Pengjiang Cheng ◽  
Zhengyun Feng ◽  
Xiaoyu Zhang
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Inflammatory Factors ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
New Strategy

Abstract Background: To investigate the role of transmembrane p24 trafficking protein 2 (TMED2) in lung adenocarcinoma (LUAD) and determine whether TMED2 knockdown could inhibit LUAD in vitro and in vivo.Methods: TIMER2.0, Kaplan-Meier plotter, gene set enrichment analysis (GSEA), Target Gene, and pan-cancer systems were used to predict the potential function of TMED2. Western blotting and immunohistochemistry were performed to analyze TMED2 expression in different tissues or cell lines. The proliferation, development, and apoptosis of LUAD were observed using a lentivirus-mediated TMED2 knockdown. Bioinformatics and western blot analysis of TMED2 against inflammation via the TLR4/NF-κB signaling pathway were conducted. Results: TMED2 expression in LUAD tumor tissues was higher than that in normal tissues and positively correlated with poor survival in lung cancer and negatively correlated with apoptosis in LUAD. The expression of TMED2 was higher in tumors or HCC827 cells. TMED2 knockdown inhibited LUAD development in vitro and in vivo and increased the levels of inflammatory factors via the TLR4/NF-κB signaling pathway. TMED2 was correlated with TME, immune score, TME-associated immune cells, their target markers, and some mechanisms and pathways, as determined using the TIMER2.0, GO, and KEGG assays.Conclusions: TMED2 may regulate inflammation in LUAD through the TLR4/NF-κB signaling pathway, and enhance the proliferation, development, and prognosis of LUAD by regulating inflammation, which provide a new strategy for treating LUAD by regulating inflammation.

scholarly journals A Prognostic Autophagy-Related Long Non-coding RNA (ARlncRNA) Signature in Acute Myeloid Leukemia (AML)

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunxia Zhao ◽  
Yulu Wang ◽  
Famei Tu ◽  
Shuai Zhao ◽  
Xiaoying Ye ◽  
...  
Keyword(s):  
Cox Regression ◽  
Survival Curve ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Risk Groups ◽  
Gene Set Enrichment Analysis ◽  
Kaplan Meier ◽  
Non Coding Rna ◽  
Novel Biomarkers ◽  
Meier Survival Curve

BackgroundSome studies have proven that autophagy and lncRNA play important roles in AML. Several autophagy related lncRNA signatures have been shown to affect the survival of patients in some other cancers. However, the role of autophagy related lncRNA in AML has not been explored yet. Hence, this study aims to find an autophagy related lncRNA signature that can affect survival for AML patients.MethodA Pearson correlation analysis, a Kaplan–Meier survival curve, a univariate cox regression, and a multivariate cox regression were performed to establish an autophagy related lncRNA signature. A univariate cox regression, a multivariate cox regression, a Kaplan–Meier survival curve, and a ROC curve were applied to confirm if the signature is an independent prognosis for AML patients. The relationship between the signature and the clinical features was explored by using a T test. Gene Set Enrichment Analysis (GSEA) was used to investigate the potential tumor related pathways.ResultsA four-autophagy related lncRNA (MIR133A1HG, AL359715.1, MIRLET7BHG, and AL356752.1) signature was established. The high risk score based on signature was related to the short survival time of AML patients. The signature was an independent factor for the prognosis for AML patients (HR = 1.684, 95% CI = 1.324–2.142, P &lt; 0.001). The signature was correlated with age, leukocyte numbers, and FAB (M3 or non-M3). The P53, IL6/JAK/STAT3, TNF-α, INF-γ, and IL2/STAT5 pathways might contribute to the differences between the risk groups based on signature in AML.ConclusionThe four autophagy related lncRNAs and their signature might be novel biomarkers for predicting the survival of AML patients. Some biological pathways might be the potential mechanisms of the signature for the survival of AML patients.

Sign in / Sign up

Export Citation Format

Share Document