scholarly journals A  novel  comprehensive immune-related gene signature as a promising survival predictor for head and neck squamous cell carcinoma

2020 ◽  
Author(s):  
Ruihua Fang ◽  
Lin Chen ◽  
Jing Liao ◽  
Jierong Luo ◽  
Chenchen Zhang ◽  
...  

Abstract Background: Head and neck squamous cell carcinoma (HNSCC), the most frequent subtype of head and neck cancer, continues to have a poor prognosis with no improvement. Growing evidence has demonstrated that the immune system plays a crucial role in the development and progression of HNSCC. The goal of our study was to develop an immune-related signature for accurately predicting the survival of HNSCC patients. Methods: Gene expression profiles were established from a total of 546 HNSCC and normal tissues to establish a training set and 83 HNSCC tissues for a validation set. Differentially expressed prognostic immune genes were identified by univariate Cox regression analysis and a corresponding network of differentially expressed transcription factors (TFs) were identified using Cytoscape. The immune-related gene signature was established and validated by univariate Cox regression analysis, least absolute shrinkage and selector operation (LASSO), and multivariate Cox regression analyses. In addition, the prognostic value of the immune-related signature was analyzed by survival and Cox regression analysis. Finally, the correlation between the immune-related signature and the immune microenvironment was established.Results: In this study, the TF-mediated network revealed that Foxp3 plays a central role in the regulatory mechanism of most immune genes. A prognostic signature based on 10 immune-related genes, which divided patients into high and low risk groups, was developed and successfully validated using two independent databases. Our prognostic signature was significantly related to worse survival and predicted prognosis in patients with different clinicopathological factors. A nomogram including clinical characteristics was also constructed for accurate prediction. Furthermore, it was determined that our prognostic signature may act as an independent factor for predicting the survival of HNSCC patients. ROC analysis also revealed that our signature had superior predictive value compared with TNM stage. As for the immune microenvironment, our signature showed a positive correlation with activated mast cells and M0 macrophages, a negative correlation with Tregs, and immune checkpoint molecules PD-1 and CLTA-4. Conclusions: Our study established an immune-related gene signature, which not only provides a promising biomarker for survival prediction, but may be evaluated as an indicator for personalized immunotherapy in patients with HNSCC.

2021 ◽  
Vol 11 ◽  
Author(s):  
Chao Zhu ◽  
Liqun Gu ◽  
Mianfeng Yao ◽  
Jiang Li ◽  
Changyun Fang

The prognosis and immunotherapy response rates are unfavorable in patients with oral squamous cell carcinoma (OSCC). The tumor microenvironment is associated with tumor prognosis and progression, and the underlying mechanisms remain unclear. We obtained differentially expressed immune-related genes from OSCC mRNA data in The Cancer Genome Atlas (TCGA) database. Overall survival-related risk signature was constructed by univariate Cox regression analysis and LASSO Cox regression analysis. The prognostic performance was validated with receiver operating characteristic (ROC) analysis and Kaplan–Meier survival curves in the TCGA and Gene Expression Omnibus (GEO) datasets. The risk score was confirmed to be an independent prognostic factor and a nomogram was built to quantify the risk of outcome for each patient. Furthermore, a negative correlation was observed between the risk score and the infiltration rate of immune cells, as well as the expression of immunostimulatory and immunosuppressive molecules. Functional enrichment analysis between different risk score subtypes detected multiple immune-related biological processes, metabolic pathways, and cancer-related pathways. Thus, the immune-related gene signature can predict overall survival and contribute to the personalized management of OSCC patients.


2020 ◽  
Vol 10 ◽  
Author(s):  
Ruiqi Zhu ◽  
Huishan Tao ◽  
Wenyi Lin ◽  
Liang Tang ◽  
Yu Hu

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by highly heterogeneous molecular lesions and cytogenetic abnormalities. Immune disorders in AML and impaired immune cell function have been found to be associated with abnormal karyotypes in AML patients. Immunotherapy has become an alternative therapeutic method that can improve the outcomes of AML patients. For solid tumors, the expression patterns of genes associated with the immune microenvironment provide valuable prognostic information. However, the prognostic roles of immune genes in AML have not been studied as yet. In this study, we identified 136 immune-related genes associated with overall survival in AML patients through a univariate Cox regression analysis using data from TCGA-AML and GTEx datasets. Next, we selected 24 hub genes from among the 136 genes based on the PPI network analysis. The 24 immune-related hub genes further underwent multivariate Cox regression analysis and LASSO regression analysis. Finally, a 6 immune-related gene signature was constructed to predict the prognosis of AML patients. The function of the hub IRGs and the relationships between hub IRGs and transcriptional factors were investigated. We found that higher levels of expression of CSK, MMP7, PSMA7, PDCD1, IKBKG, and ISG15 were associated with an unfavorable prognosis of AML patients. Meanwhile, patients in the TCGA-AML datasets were divided into a high risk score group and a low risk score group, based on the median risk score value. Patients in the high risk group tended to show poorer prognosis [P = 0.00019, HR = 1.89 (1.26–2.83)]. The area under the curve (AUC) was 0.6643. Multivariate Cox Regression assay confirmed that the 6 IRG signature was an independent prognostic factor for AML. The prognostic role of the immune related-gene signature was further validated using an independent AML dataset, GSE37642. In addition, patients in the high risk score group in the TCGA dataset were found to be of an advanced age, IDH mutation, and M5 FAB category. These results suggested that the proposed immune related-gene signature may serve as a potential prognostic tool for AML patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Qi ◽  
Rui Wang ◽  
Yuxin Lin ◽  
Donghui Yan ◽  
Jiachen Zuo ◽  
...  

BackgroundColon cancer (CC) is a common gastrointestinal malignant tumor with high heterogeneity in clinical behavior and response to treatment, making individualized survival prediction challenging. Ferroptosis is a newly discovered iron-dependent cell death that plays a critical role in cancer biology. Therefore, identifying a prognostic biomarker with ferroptosis-related genes provides a new strategy to guide precise clinical decision-making in CC patients.MethodsAlteration in the expression profile of ferroptosis-related genes was initially screened in GSE39582 dataset involving 585 CC patients. Univariate Cox regression analysis and LASSO-penalized Cox regression analysis were combined to further identify a novel ferroptosis-related gene signature for overall survival prediction. The prognostic performance of the signature was validated in the GSE17536 dataset by Kaplan-Meier survival curve and time-dependent ROC curve analyses. Functional annotation of the signature was explored by integrating GO and KEGG enrichment analysis, GSEA analysis and ssGSEA analysis. Furthermore, an outcome risk nomogram was constructed considering both the gene signature and the clinicopathological features.ResultsThe prognostic signature biomarker composed of 9 ferroptosis-related genes accurately discriminated high-risk and low-risk patients with CC in both the training and validation datasets. The signature was tightly linked to clinicopathological features and possessed powerful predictive ability for distinct clinical subgroups. Furthermore, the risk score was confirmed to be an independent prognostic factor for CC patients by multivariate Cox regression analysis (p < 0.05). Functional annotation analyses showed that the prognostic signature was closely correlated with pivotal cancer hallmarks, particularly cell cycle, transcriptional regulation, and immune-related functions. Moreover, a nomogram with the signature was also built to quantify outcome risk for each patient.ConclusionThe novel ferroptosis-related gene signature biomarker can be utilized for predicting individualized prognosis, optimizing survival risk assessment and facilitating personalized management of CC patients.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunlei Wu ◽  
Quanteng Hu ◽  
Dehua Ma

AbstractLung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. We downloaded the gene expression profile and immune-related gene set from the TCGA and ImmPort database, respectively, to establish immune-related gene pairs (IRGPs). Then, IRGPs were subjected to univariate Cox regression analysis, LASSO regression analysis, and multivariable Cox regression analysis to screen and develop an IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from the GEO set was used to validate this signature. The relationship of 22 tumor-infiltrating immune cells (TIICs) to the immune risk score was also investigated. An IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in the TCGA set was 0.867 and 0.870, respectively. Similar results were observed in the AUCs of GEO set 1, 2 and 3 (GEO set 1 [1-year: 0.819; 3-year: 0.803]; GEO set 2 [1-year: 0.834; 3-year: 0.870]; GEO set 3 [1-year: 0.955; 3-year: 0.827]). Survival analysis demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that the risk score was an independent prognostic factor. The immune risk score was highly associated with several TIICs (Plasma cells, memory B cells, resting memory CD4 T cells, and activated NK cells). We developed a novel IRGPs signature for predicting 1- and 3- year overall survival in LUAD, which would be helpful for prognosis assessment of LUAD.


2021 ◽  
Vol 20 ◽  
pp. 153303382110414
Author(s):  
Xiaoyong Li ◽  
Jiaqong Lin ◽  
Yuguo pan ◽  
Peng Cui ◽  
Jintang Xia

Background: Liver progenitor cells (LPCs) play significant roles in the development and progression of hepatocellular carcinoma (HCC). However, no studies on the value of LPC-related genes for evaluating HCC prognosis exist. We developed a gene signature of LPC-related genes for prognostication in HCC. Methods: To identify LPC-related genes, we analyzed mRNA expression arrays from a dataset (GSE57812 & GSE 37071) containing LPCs, mature hepatocytes, and embryonic stem cell samples. HCC RNA-Seq data from The Cancer Genome Atlas (TCGA) were used to explore the differentially expressed genes (DEGs) related to prognosis through DEG analysis and univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed to construct the LPC-related gene prognostic model in the TCGA training dataset. This model was validated in the TCGA testing set and an external dataset (International Cancer Genome Consortium [ICGC] dataset). Finally, we investigated the relationship between this prognostic model with tumor-node-metastasis stage, tumor grade, and vascular invasion of HCC. Results: Overall, 1770 genes were identified as LPC-related genes, of which 92 genes were identified as DEGs in HCC tissues compared with normal tissues. Furthermore, we randomly assigned patients from the TCGA dataset to the training and testing cohorts. Twenty-six DEGs correlated with overall survival (OS) in the univariate Cox regression analysis. Lasso and multivariate Cox regression analyses were performed in the TCGA training set, and a 3-gene signature was constructed to stratify patients into 2 risk groups: high-risk and low-risk. Patients in the high-risk group had significantly lower OS than those in the low-risk group. Receiver operating characteristic curve analysis confirmed the signature's predictive capacity. Moreover, the risk score was confirmed to be an independent predictor for patients with HCC. Conclusion: We demonstrated that the LPC-related gene signature can be used for prognostication in HCC. Thus, targeting LPCs may serve as a therapeutic alternative for HCC.


2021 ◽  
Author(s):  
Jixiang Cao ◽  
Xi Chen ◽  
Guang Lu ◽  
Haowei Wang ◽  
Xinyu Zhang ◽  
...  

Abstract Background: Cholangiocarcinoma (CCA) is the most common malignancy of the biliary tract with a dismal prognosis. Increasing evidence suggests that tumor microenvironment (TME) is closely associated with cancer prognosis. However, the prognostic signature for CCA based on TME has not yet been reported. This study aimed to develop a TME-related prognostic signature for accurately predicting the prognosis of patients with CCA. Methods: Based on the TCGA database, we calculated the stromal and immune scores using the ESTIMATE algorithm to assess TME in stromal and immune cells derived from CCA. TME-related differentially expressed genes were identified, followed by functional enrichment analysis and PPI network analysis. Univariate Cox regression analysis, Lasso Cox regression model and multivariable Cox regression analysis were performed to identify and construct the TME-related prognostic gene signature. Gene Set Enrichment Analyses (GSEA) was performed to further investigate the potential molecular mechanisms. The correlations between the risk scores and tumor infiltration immune cells were analyzed using Tumor Immune Estimation Resource (TIMER) database. Results: A total of 784 TME-related differentially expressed genes (DEGs) were identified, which were mainly enriched in immune-related processes and pathways. Among these TME-related DEGs, A novel two‑gene signature (including GAD1 and KLRB1) was constructed for CCA prognosis prediction. The AUC of the prognostic model for predicting the survival of patients at 1-, 2-, and 3- years was 0.811, 0.772, and 0.844, respectively. Cox regression analysis showed that the two‑gene signature was an independent prognostic factor. Based on the risk scores of the prognostic model, CCA patients were divided into high- and low-risk groups, and patients with high-risk score had shorter survival time than those with low-risk score. Furthermore, we found that the risk scores were negatively correlated with TME-scores and the number of several tumor infiltration immune cells, including B cells and CD4+ T cells. Conclusion: Our study established a novel TME-related gene signature to predict the prognosis of patients with CCA. This might provide a new understanding of the potential relationship between TME and CCA prognosis, and serve as a prognosis stratification tool for guiding personalized treatment of CCA patients.


2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yang Li ◽  
Rongrong Sun ◽  
Rui Li ◽  
Yonggang Chen ◽  
He Du

Evidence is increasingly indicating that circular RNAs (circRNAs) are closely involved in tumorigenesis and cancer progression. However, the function and application of circRNAs in lung adenocarcinoma (LUAD) are still unknown. In this study, we constructed a circRNA-associated competitive endogenous RNA (ceRNA) network to investigate the regulatory mechanism of LUAD procession and further constructed a prognostic signature to predict overall survival for LUAD patients. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were selected to construct the ceRNA network. Based on the TargetScan prediction tool and Pearson correlation coefficient, we constructed a circRNA-associated ceRNA network including 11 DEcircRNAs, 8 DEmiRNAs, and 49 DEmRNAs. GO and KEGG enrichment indicated that the ceRNA network might be involved in the regulation of GTPase activity and endothelial cell differentiation. After removing the discrete points, a PPI network containing 12 DEmRNAs was constructed. Univariate Cox regression analysis showed that three DEmRNAs were significantly associated with overall survival. Therefore, we constructed a three-gene prognostic signature for LUAD patients using the LASSO method in the TCGA-LUAD training cohort. By applying the signature, patients could be categorized into the high-risk or low-risk subgroups with significant survival differences (HR: 1.62, 95% CI: 1.12-2.35, log-rank p = 0.009 ). The prognostic performance was confirmed in an independent GEO cohort (GSE42127, HR: 2.59, 95% CI: 1.32-5.10, log-rank p = 0.004 ). Multivariate Cox regression analysis proved that the three-gene signature was an independent prognostic factor. Combining the three-gene signature with clinical characters, a nomogram was constructed. The primary and external verification C -indexes were 0.717 and 0.716, respectively. The calibration curves for the probability of 3- and 5-year OS showed significant agreement between nomogram predictions and actual observations. Our findings provided a deeper understanding of the circRNA-associated ceRNA regulatory mechanism in LUAD pathogenesis and further constructed a useful prognostic signature to guide personalized treatment of LUAD patients.


2020 ◽  
Author(s):  
Chunlei Wu ◽  
Quanteng Hu ◽  
Dehua Ma

Abstract Background Lung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. The aim of this study was to establish an immune-related gene pairs (IRGPs) signature for predicting the prognosis of LUAD patients.Methods We downloaded the gene expression profile and immune-related gene set from TCGA and ImmPort database, respectively, to establish IRGPs. Then, IRGPs subjected to univariate Cox regression analysis, LASSO regression analysis and multivariable Cox regression analysis to screen and develop a IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from GEO was used to validate this signature.Results A IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in TCGA set was 0.867 and 0.870, respectively. Similar result was observed in the AUC of GEO set and Total set (GEO set [1-year: 0.819; 3-years: 0.803]; Total set [1-year: 0.845; 3-years: 0.801]). Survival analysis of three sets demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that risk score was independent prognostic factors.Conclusions We developed a novel IRGPs signature for predicting prognosis of LUAD.


2021 ◽  
Vol 8 ◽  
Author(s):  
Zhengjie Xu ◽  
Suxiao Jiang ◽  
Juan Ma ◽  
Desheng Tang ◽  
Changsheng Yan ◽  
...  

Background: Breast cancer (BC) is a heterogeneous malignant tumor, leading to the second major cause of female mortality. This study aimed to establish an in-depth relationship between ferroptosis-related LncRNA (FRlncRNA) and the prognosis as well as immune microenvironment of the patients with BC.Methods: We downloaded and integrated the gene expression data and the clinical information of the patients with BC from The Cancer Genome Atlas (TCGA) database. The co-expression network analysis and univariate Cox regression analysis were performed to screen out the FRlncRNAs related to prognosis. A cluster analysis was adopted to explore the difference of immune microenvironment between the clusters. Furthermore, we determined the optimal survival-related FRLncRNAs for final signature by LASSO Cox regression analysis. Afterward, we constructed and validated the prediction models, which were further tested in different subgroups.Results: A total of 31 FRLncRNAs were filtrated as prognostic biomarkers. Two clusters were determined, and C1 showed better prognosis and higher infiltration level of immune cells, such as B cells naive, plasma cells, T cells CD8, and T cells CD4 memory activated. However, there were no significantly different clinical characters between the clusters. Gene Set Enrichment Analysis (GSEA) revealed that some metabolism-related pathways and immune-associated pathways were exposed. In addition, 12 FRLncRNAs were determined by LASSO analysis and used to construct a prognostic signature. In both the training and testing sets, patients in the high-risk group had a worse survival than the low-risk patients. The area under the curves (AUCs) of receiver operator characteristic (ROC) curves were about 0.700, showing positive prognostic capacity. More notably, through the comprehensive analysis of heatmap, we regarded LINC01871, LINC02384, LIPE-AS1, and HSD11B1-AS1 as protective LncRNAs, while LINC00393, AC121247.2, AC010655.2, LINC01419, PTPRD-AS1, AC099329.2, OTUD6B-AS1, and LINC02266 were classified as risk LncRNAs. At the same time, the patients in the low-risk groups were more likely to be assigned to C1 and had a higher immune score, which were consistent with a better prognosis.Conclusion: Our research indicated that the ferroptosis-related prognostic signature could be used as novel biomarkers for predicting the prognosis of BC. The differences in the immune microenvironment exhibited by BC patients with different risks and clusters suggested that there may be a complementary synergistic effect between ferroptosis and immunotherapy.


2020 ◽  
Author(s):  
Chunlei Wu ◽  
Quanteng Hu ◽  
Dehua Ma

Abstract Background: Lung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. The aim of this study was to establish an immune-related gene pairs (IRGPs) signature for predicting the prognosis of LUAD patients.Methods: We downloaded the gene expression profile and immune-related gene set from TCGA and ImmPort database, respectively, to establish IRGPs. Then, IRGPs were subjected to univariate Cox regression analysis, LASSO regression analysis and multivariable Cox regression analysis to screen and develop a IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from GEO was used to validate this signature. Results: A IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in TCGA set was 0.867 and 0.870, respectively. Similar result was observed in the AUC of GEO set and Total set (GEO set [1-year: 0.819; 3-years: 0.803]; Total set [1-year: 0.845; 3-years: 0.801]). Survival analysis of three sets demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that risk score was independent prognostic factors.Conclusions: We developed a novel IRGPs signature for predicting prognosis of LUAD.


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