scholarly journals Significance of Tumor Mutation Burden Combined With Immune Infiltrates in the Progression and Prognosis of Advanced Gastric Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiong Guo ◽  
Xiaolong Liang ◽  
Yujun Wang ◽  
Anqi Cheng ◽  
Han Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Visual Analysis ◽  
Risk Model ◽  
Cox Regression ◽  
Expression Patterns ◽  
Clinicopathological Parameters ◽  
Tumor Mutation Burden ◽  
Cox Regression Analysis ◽  
Mutation Burden

Gastric cancer (GC) is a serious malignant tumor with high mortality and poor prognosis. The prognosis and survival are much worse for advanced gastric cancer (AGC). Recently, immunotherapy has been widely promoted for AGC patients, and studies have shown that tumor mutation burden (TMB) is closely related to immunotherapy response. Here, RNA-seq data, matched clinical information, and MAF files were downloaded from the cancer genome atlas (TCGA)-STAD project in the TCGA database. The collation and visual analysis of mutation data were implemented by the “maftools” package in R. We calculated the TMB values for AGC patients and divided the patients into high- and low-TMB groups according to the median value of TMB. Then, the correlation between high or low TMB and clinicopathological parameters was calculated. Next, we examined the differences in gene expression patterns between the two groups by using the “limma” R package and identified the immune-related genes among the DEGs. Through univariate Cox regression analysis, 15 genes related to prognosis were obtained. Furthermore, the two hub genes (APOD and SLC22A17) were used to construct a risk model to evaluate the prognosis of AGC patients. ROC and survival curves and GEO data were used as a validation set to verify the reliability of this risk model. In addition, the correlation between TMB and tumor-infiltrating immune cells was examined. In conclusion, our results suggest that AGC patients with high TMB have a better prognosis. By testing the patient’s TMB, we could better guide immunotherapy and understand patient response to immunotherapy.

scholarly journals A Tumor Progression Related 7-Gene Signature Indicates Prognosis and Tumor Immune Characteristics of Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Fen Liu ◽  
Zongcheng Yang ◽  
Lixin Zheng ◽  
Wei Shao ◽  
Xiujie Cui ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
High Risk ◽  
Cancer Progression ◽  
Risk Score ◽  
Risk Model ◽  
Cox Regression ◽  
Hub Genes ◽  
Cox Regression Analysis ◽  
High Risk Patients ◽  
Risk Patients

BackgroundGastric cancer is a common gastrointestinal malignancy. Since it is often diagnosed in the advanced stage, its mortality rate is high. Traditional therapies (such as continuous chemotherapy) are not satisfactory for advanced gastric cancer, but immunotherapy has shown great therapeutic potential. Gastric cancer has high molecular and phenotypic heterogeneity. New strategies for accurate prognostic evaluation and patient selection for immunotherapy are urgently needed.MethodsWeighted gene coexpression network analysis (WGCNA) was used to identify hub genes related to gastric cancer progression. Based on the hub genes, the samples were divided into two subtypes by consensus clustering analysis. After obtaining the differentially expressed genes between the subtypes, a gastric cancer risk model was constructed through univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis. The differences in prognosis, clinical features, tumor microenvironment (TME) components and immune characteristics were compared between subtypes and risk groups, and the connectivity map (CMap) database was applied to identify potential treatments for high-risk patients.ResultsWGCNA and screening revealed nine hub genes closely related to gastric cancer progression. Unsupervised clustering according to hub gene expression grouped gastric cancer patients into two subtypes related to disease progression, and these patients showed significant differences in prognoses, TME immune and stromal scores, and suppressive immune checkpoint expression. Based on the different expression patterns between the subtypes, we constructed a gastric cancer risk model and divided patients into a high-risk group and a low-risk group based on the risk score. High-risk patients had a poorer prognosis, higher TME immune/stromal scores, higher inhibitory immune checkpoint expression, and more immune characteristics suitable for immunotherapy. Multivariate Cox regression analysis including the age, stage and risk score indicated that the risk score can be used as an independent prognostic factor for gastric cancer. On the basis of the risk score, we constructed a nomogram that relatively accurately predicts gastric cancer patient prognoses and screened potential drugs for high-risk patients.ConclusionsOur results suggest that the 7-gene signature related to tumor progression could predict the clinical prognosis and tumor immune characteristics of gastric cancer.

scholarly journals A Prognostic Nomogram Model Based on mRNA Expression of DNA Methylation-Driven Genes for Gastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Zuhua Chen ◽  
Bo Liu ◽  
Minxiao Yi ◽  
Hong Qiu ◽  
Xianglin Yuan
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Mrna Expression ◽  
Risk Model ◽  
Cox Regression ◽  
Risk Group ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Clinicopathological Parameters ◽  
Dna Hypomethylation

PurposeThe exploration and interpretation of DNA methylation-driven genes might contribute to molecular classification, prognostic prediction and therapeutic choice. In this study, we built a prognostic risk model via integrating analysis of the transcriptome and methylation profile for patients with gastric cancer (GC).MethodsThe mRNA expression profiles, DNA methylation profiles and corresponding clinicopathological information of 415 GC patients were downloaded from The Cancer Genome Atlas (TCGA). Differential expression and correlation analysis were performed to identify DNA methylation-driven genes. The candidate genes were selected by univariate Cox regression analyses followed by the least absolute shrinkage and selection operator (LASSO) regression. A prognostic risk nomogram model was then built together with clinicopathological parameters.Results5 DNA methylation-driven genes (CXCL3, F5, GNAI1, GAMT and GHR) were identified by integrated analyses and selected to construct the prognostic risk model with clinicopathological parameters. High expression and low DNA hypermethylation of F5, GNAI1, GAMT and GHR, as well as low expression and high DNA hypomethylation of CXCL3 were significantly associated with poor prognosis rates, respectively. The high-risk group showed a significantly shorter prognosis than the low-risk group in the TCGA dataset (HR = 0.212, 95% CI = 0.139–0.322, P = 2e-15). The final nomogram model showed high predictive efficiency and consistency in the training and validation group.ConclusionWe construct and validate a prognostic nomogram model for GC based on five DNA methylation-driven genes with high performance and stability. This nomogram model might be a powerful tool for prognosis evaluation in the clinic and also provided novel insights into the epigenetics in GC.

scholarly journals KK-LC-1 may be an effective prognostic biomarker for gastric cancer

2020 ◽  
Author(s):  
Jun Ji ◽  
Jiahui Chen ◽  
Anqiang Wang ◽  
Wei Zhang ◽  
Hongge Ju ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Cox Regression ◽  
Staining Intensity ◽  
Good Prognosis ◽  
Clinicopathological Parameters ◽  
Chi Square ◽  
Clinical Prognosis ◽  
Cox Regression Analysis ◽  
Normal Tissues

Abstract Background: To detect the expression of Kita-Kyushu lung cancer antigen-1 (KK-LC-1) in gastric cancer (GC) specimens and analyze the associations between KK-LC-1 expression and clinicopathological parameters and clinical prognosis. Methods: A total of 94 patients with GC who underwent surgical resection were enrolled in this study. The expression of KK-LC-1 in GC tissues was detected by immunohistochemistry. The assessment of KK-LC-1 expression was conducted using the H-scoring system. H-score was calculated by the multiplication of the overall staining intensity with the percentage of positive cells. The expression of KK-LC-1 in the cytoplasm and was scored to achieve respective H-score values. The correlations between KK-LC-1 expression and clinicopathological parameters and clinical prognosis were analyzed using Chi-square test, Kaplan-Meier method and Cox regression. Results: In the cytoplasm, the expression of KK-LC-1 in tumor tissues was significantly higher than that in normal tissues (P < 0.001, respectively). Using the median H-score as the cutoff value, it was discovered that, GC patients with higher levels of KK-LC-1expression in the cytoplasm, had favorable overall survival (P =0.016), and it was still statistically meaningful in Cox regression analysis. At the same time, the study found that there was a negative correlation between KK-LC-1’s protein expression and the pathological grade of the tumor (P = 0.036). Conclusions: Our research data shows that KK-LC-1’s expression in GC is higher than that of normal tissues, which is associated with a longer overall survival in GC. KK-LC-1 can be used as a biomarker for GC patients with good prognosis.

scholarly journals Comprehensive Analysis and Prognosis Prediction of N6-methyladenosine-related Lncrnas in Immune Microenvironment Infiltration of Gastric Cancer

2021 ◽  
Author(s):  
Jianfeng Huang ◽  
Wenzheng Chen ◽  
Changyu Chen ◽  
Tao Xiao ◽  
Zhigang Jie
Keyword(s):  
Gastric Cancer ◽  
Risk Model ◽  
Cox Regression ◽  
Cytotoxic T Lymphocyte ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Rna Modification ◽  
Consensus Clustering ◽  
Immune Microenvironment ◽  
Cox Regression Analysis

Abstract BackgroundN6-methyladenosine (m6A) RNA modification plays an important role in regulating tumor microenvironment (TME) infiltration. However, the relationship between the expression pattern of m6A-related long non-coding RNAs (lncRNAs) and the immune microenvironment of gastric cancer (GC) is unclear. MethodsIn this study, 23 m6A-related lncRNAs were identified by Pearson’s correlation analysis and univariate Cox regression analysis. According to the expression of these lncRNAs, we identified two distinct molecular clusters by consensus clustering and compared the differences of the TME and enriched pathways between the two clusters. We further constructed a prognostic risk signature and verified it using The Cancer Genome Atlas training and testing cohorts. ResultsThe results showed that cluster 1 was associated with tumor-related and immune activation-related pathways. In addition, cluster 1 was also associated with higher ImmuneScore, StromalScore, and ESTIMATEScore. The results of the stratified survival analysis and independent prognosis analysis indicated that the risk signature is an independent prognostic indicator for patients with GC. In addition, it can effectively predict survival status in patients with different clinical characteristics. Furthermore, our risk model showed that low risk scores were significantly correlated with high expression of programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), as well as sensitivity to chemotherapeutic drugs (e.g., paclitaxel and oxaliplatin). ConclusionsThis evidence contributes to our understanding of the regulation of TME infiltration by m6A-related lncRNAs and my lead to more effective immunotherapy and chemotherapy for patients with GC.

scholarly journals Systematic Analyses of a Chemokine Family-Based Risk Model Predicting Clinical Outcome and Immunotherapy Response in Lung Adenocarcinoma

2021 ◽  
Vol 30 ◽  
pp. 096368972110550
Author(s):  
Jiarui Chen ◽  
Xingyu Liu ◽  
Qiuji Wu ◽  
Xueping Jiang ◽  
Zihang Zeng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Risk Model ◽  
Cox Regression ◽  
Expression Patterns ◽  
Low Risk ◽  
The Cancer Genome Atlas ◽  
Cox Regression Analysis ◽  
Family Based ◽  
Chemokine Family

Chemokines exhibited complicated functions in antitumor immunity, with their expression profile and clinical importance of lung adenocarcinoma (LUAD) patients remaining largely undetermined. This study aimed to explore the expression patterns of chemokine family in LUAD and construct a predictive chemokine family-based signature. A total of 497 samples were downloaded from the Cancer Genome Atlas (TCGA) data portal as the training set, and the combination of 4 representative Gene Expression Omnibus (GEO) datasets, including GSE30219, GSE50081, GSE37745, and GSE31210, were utilized as the validation set. A three gene-based signature was constructed using univariate and stepwise multivariate Cox regression analysis, classifying patients into high and low risk groups according to the overall survival. The independent GEO datasets were utilized to validate this signature. Another multivariate analysis revealed that this signature remained an independent prognostic factor in LUAD patients. Furthermore, patients in the low risk group featured immunoactive tumor microenvironment (TME), higher IPS scores and lower TIDE scores, and was regarded as the potential beneficiaries of immunotherapy. Finally, the role of risky CCL20 was validated by immunohistochemistry (IHC), and patients possessed higher CCL20 expression presented shorter overall survival ( P = 0.011).

scholarly journals m6A RNA Methylation Regulators Impact Prognosis and Tumor Microenvironment in Renal Papillary Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Lianze Chen ◽  
Baohui Hu ◽  
Xinyue Song ◽  
Lin Wang ◽  
Mingyi Ju ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Risk Model ◽  
Cox Regression ◽  
Expression Patterns ◽  
The Cancer Genome Atlas ◽  
Rna Modification ◽  
Lasso Regression ◽  
Cox Regression Analysis ◽  
Rna Methylation

Accumulating evidence has proven that N6-methyladenosine (m6A) RNA methylation plays an essential role in tumorigenesis. However, the significance of m6A RNA methylation modulators in the malignant progression of papillary renal cell carcinoma (PRCC) and their impact on prognosis has not been fully analyzed. The present research set out to explore the roles of 17 m6A RNA methylation regulators in tumor microenvironment (TME) of PRCC and identify the prognostic values of m6A RNA methylation regulators in patients afflicted by PRCC. We investigated the different expression patterns of the m6A RNA methylation regulators between PRCC tumor samples and normal tissues, and systematically explored the association of the expression patterns of these genes with TME cell-infiltrating characteristics. Additionally, we used LASSO regression to construct a risk signature based upon the m6A RNA methylation modulators. Two-gene prognostic risk model including IGF2BP3 and HNRNPC was constructed and could predict overall survival (OS) of PRCC patients from the Cancer Genome Atlas (TCGA) dataset. The prognostic signature-based risk score was identified as an independent prognostic indicator in Cox regression analysis. Moreover, we predicted the three most significant small molecule drugs that potentially inhibit PRCC. Taken together, our study revealed that m6A RNA methylation regulators might play a significant role in the initiation and progression of PRCC. The results might provide novel insight into exploration of m6A RNA modification in PRCC and provide essential guidance for therapeutic strategies.

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.

Use of circulating tumor cells to predict response to chemotherapy in patients with advanced gastric cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 43-43
Author(s):  
S. Matsusaka ◽  
K. Chin ◽  
N. Mizunuma ◽  
M. Ogura ◽  
M. Suenaga ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cox Regression ◽  
Performance Status ◽  
Univariate Analysis ◽  
Eastern Cooperative Oncology Group ◽  
Cox Regression Analysis ◽  
Response To Chemotherapy

43 Background: The purpose of this study was to quantify circulating tumor cells (CTCs) in advanced gastric cancer (AGC) patients, and to demonstrate the role of CTCs in cancer therapy. The purpose of this study was to identify CTC threshold proposal for determining response to chemotherapy in AGC. Methods: From November 2007 to June 2009, fifty-two patients with AGC were enrolled into a prospective study. All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital and provided informed consent. The study population consisted of patients of aged 18 years or older with histologically proven AGC. Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2; adequate organ function. The subjects were five patients treated with S-1 (40 mg/m2, twice daily, days 1-28, repeated every 6 weeks), twenty-six patients treated with S-1 plus CDDP (S-1 40 mg/m2, twice daily, days 1-21, CDDP 60 mg/m2, day 8, repeated every 5 weeks), and twenty-one patients treated with paclitaxel (80 mg/m2, weekly). CTCs of whole blood at baseline, two weeks and four weeks after initiation of chemotherapy, were isolated and enumerated using immunomagnetics. Results: Patients with ≥4 CTCs at two-week points and four-week points had a shorter median PFS (1.4, 1.4 months, respectively), than those with the median PFS of <4 CTCs (4.9, 5.0 months, respectively) (p<0.001, p<0.001, respectively). Patients with ≥4 CTCs at two-week points and four-week points had shorter median OS (3.5, 4.0 months, respectively) than those with the median PFS of <4 CTCs (11.7, 11.4 months, respectively) (p<0.001, p=0.001, respectively). In univariate analysis, PS, treatment regimen, Line of chemotherapy, and CTC levels at 2 weeks and 4 weeks predicted PFS and OS. In order to evaluate the independent predictive effect of chemotherapy, multivariate Cox regression analysis was carried out. CTC levels at 2 weeks and 4 weeks were the strongest predictors. Conclusions: A threshold of lower than 4 CTC/7.5 ml at 2 weeks and 4 weeks was a significant predictor of the outcome for AGC patients treated with S-1 based regimen or paclitaxel regimen. No significant financial relationships to disclose.

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 CD169 Expression on Lymph Node Macrophages Predicts in Patients With Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Keiichiro Kumamoto ◽  
Takashi Tasaki ◽  
Koji Ohnishi ◽  
Michihiko Shibata ◽  
Shohei Shimajiri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Lymph Node ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Advanced Gastric Cancer ◽  
Cox Regression ◽  
Regional Lymph Nodes ◽  
Cox Regression Analysis ◽  
Anti Cancer ◽  
Cancer Tissues

The induction of an anti-cancer immune responses is potentially associated with the efficacy of anti-cancer therapy. Recent studies have indicated that sinus macrophages in regional lymph nodes are involved in anti-cancer immune responses in the cancer microenvironment. In the present study, we investigated the correlation between lymphocyte infiltration in cancer tissues and macrophage activation in regional lymph nodes. We retrospectively identified 294 patients with gastric cancer who underwent surgery from 2008 to 2012. Using immunohistochemistry, we evaluated CD169-expression on CD68-positive macrophages, and the density of CD8-postive lymphocytes in tumor microenvironment. We statistically examined the correlation between CD169 and CD8 expression, and performed Cox regression analysis of potential prognostic factors, including CD169 and CD8 expression, for cancer-specific survival (CSS) in patients with total and advanced gastric cancer. CD169 overexpression in lymph node sinus macrophages (LySMs) was positively correlated to the density of CD8-positive lymphocytes in primary cancer tissues (R = 0.367, p &lt; 0.001). A high density of CD8-positive T lymphocytes in the primary site and a high level of CD169 expression in LySMs were independently associated with greater CSS in patients with total and advanced gastric cancer (p &lt; 0.05 for all). The expression on CD169 in LySMs is a predictor of a favorable clinical course in patients with gastric cancer, and might be useful for evaluating anti-cancer immune responses.

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