scholarly journals A Novel Ferroptosis-Related Gene Signature Robustly Predicts Clinical Prognosis And Tumor Immunity in Patients With Kidney Renal Clear Cell Carcinoma

Author(s):  
Wei Song ◽  
Weiting Kang ◽  
Qi Zhang

Abstract Objective: This study aimed to construct a ferroptosis-related gene signature to predict clinical prognosis and tumor immunity in patients with kidney renal clear cell carcinoma (KIRC).Methods: The mRNA expression profiles and corresponding clinical data of KIRC patients were downloaded from The Cancer Genome Atlas (TCGA), which were randomly divided into training (398 patients) and validation set (132 patients). The iron death related (IDR) prediction model was constructed based on training set and 60 ferroptosis-related genes from previous literatures, followed by prognostic performance evaluation and verification using the validation set. Moreover, functional enrichment, immune cell infiltration, metagene clusters correlation, and TIDE scoring analyses were performed. Results: In total, 23 ferroptosis-related genes were significantly associated with overall survival (OS). The IDR prediction model (a 10-gene signature) was then constructed to stratify patients into two risk groups. The OS of KIRC patients with high-risk scores was significantly shorter than those with low-risk scores. Moreover, the risk score was confirmed as an independent prognostic predictor for OS. The positive and negative correlated genes with this model were significantly enriched in p53 signaling pathway, and cGMP-PKG signaling pathway. The patients in the high-risk group had higher ratios of plasma cells, T cells CD8, and T cells regulatory Tregs. Furthermore, IgG, HCK, LCK, and Interferson metagenes were significantly correlated with risk score. By TIDE score analysis, patients in the high-risk group could benefit from immunotherapy.Conclusions: The identified ferroptosis-related gene signature is significantly correlated with clinical prognosis and immune immunity in KIRC patients.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pankaj Ahluwalia ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil Sahajpal ◽  
Vamsi Kota ◽  
...  

AbstractComplex interactions in tumor microenvironment between ECM (extra-cellular matrix) and cancer cell plays a central role in the generation of tumor supportive microenvironment. In this study, the expression of ECM-related genes was explored for prognostic and immunological implication in clear cell renal clear cell carcinoma (ccRCC). Out of 964 ECM genes, higher expression (z-score > 2) of 35 genes showed significant association with overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS). On comparison to normal tissue, 12 genes (NUDT1, SIGLEC1, LRP1, LOXL2, SERPINE1, PLOD3, ZP3, RARRES2, TGM2, COL3A1, ANXA4, and POSTN) showed elevated expression in kidney tumor (n = 523) compared to normal (n = 100). Further, Cox proportional hazard model was utilized to develop 12 genes ECM signature that showed significant association with overall survival in TCGA dataset (HR = 2.45; 95% CI [1.78–3.38]; p < 0.01). This gene signature was further validated in 3 independent datasets from GEO database. Kaplan–Meier log-rank test significantly associated patients with elevated expression of this gene signature with a higher risk of mortality. Further, differential gene expression analysis using DESeq2 and principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters between ECM-rich high-risk and ECM-poor low-risk patients. Geneset enrichment analysis (GSEA) identified significant perturbations in homeostatic kidney functions in the high-risk group. Further, higher infiltration of immunosuppressive T-reg and M2 macrophages was observed in high-risk group patients. The present study has identified a prognostic signature with associated tumor-promoting immune niche with clinical utility in ccRCC. Further exploration of ECM dynamics and validation of this gene signature can assist in design and application of novel therapeutic approaches.


2021 ◽  
Vol 12 ◽  
Author(s):  
Susu Zheng ◽  
Xiaoying Xie ◽  
Xinkun Guo ◽  
Yanfang Wu ◽  
Guobin Chen ◽  
...  

Pyroptosis is a novel kind of cellular necrosis and shown to be involved in cancer progression. However, the diverse expression, prognosis and associations with immune status of pyroptosis-related genes in Hepatocellular carcinoma (HCC) have yet to be analyzed. Herein, the expression profiles and corresponding clinical characteristics of HCC samples were collected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then a pyroptosis-related gene signature was built by applying the least absolute shrinkage and selection operator (LASSO) Cox regression model from the TCGA cohort, while the GEO datasets were applied for verification. Twenty-four pyroptosis-related genes were found to be differentially expressed between HCC and normal samples. A five pyroptosis-related gene signature (GSDME, CASP8, SCAF11, NOD2, CASP6) was constructed according to LASSO Cox regression model. Patients in the low-risk group had better survival rates than those in the high-risk group. The risk score was proved to be an independent prognostic factor for overall survival (OS). The risk score correlated with immune infiltrations and immunotherapy responses. GSEA indicated that endocytosis, ubiquitin mediated proteolysis and regulation of autophagy were enriched in the high-risk group, while drug metabolism cytochrome P450 and tryptophan metabolism were enriched in the low-risk group. In conclusion, our pyroptosis-related gene signature can be used for survival prediction and may also predict the response of immunotherapy.


2021 ◽  
Vol 12 ◽  
Author(s):  
Junli Wang ◽  
Qi Zhang ◽  
Fukang Shi ◽  
Dipesh Kumar Yadav ◽  
Zhengtao Hong ◽  
...  

Purpose: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant diseases worldwide and has a poor prognosis. Gene-based prognostic models have been reported to predict the overall survival of patients with HCC. Unfortunately, most of the genes used in earlier prognostic models lack prospective validation and, thus, cannot be used in clinical practice.Methods: Candidate genes were selected from GEPIA (Gene Expression Profiling Interactive Analysis), and their associations with patients’ survival were confirmed by RT-PCR using cDNA tissue microarrays established from patients with HCC after radical resection. A multivariate Cox proportion model was used to calculate the coefficient of corresponding gene. The expression of seven genes of interest (MKI67, AR, PLG, DNASE1L3, PTTG1, PPP1R1A, and TTR) with two reference genes was defined to calculate a risk score which determined groups of different risks.Results: Our risk scoring efficiently classified patients (n = 129) with HCC into a low-, intermediate-, and high-risk group. The three groups showed meaningful distinction of 3-year overall survival rate, i.e., 88.9, 74.5, and 20.6% for the low-, intermediate-, and high-risk group, respectively. The prognostic prediction model of risk scores was subsequently verified using an independent prospective cohort (n = 77) and showed high accuracy.Conclusion: Our seven-gene signature model performed excellent long-term prediction power and provided crucially guiding therapy for patients who are not a candidate for surgery.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinyuan Shi ◽  
Pu Wu ◽  
Lei Sheng ◽  
Wei Sun ◽  
Hao Zhang

Abstract Background Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC), accounting for more than 80% of all cases. Ferroptosis is a novel iron-dependent and Reactive oxygen species (ROS) reliant type of cell death which is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated that ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in PTC remains unclear. This study aims at exploring the expression of ferroptosis-related genes (FRG) and their prognostic values in PTC. Methods A ferroptosis-related gene signature was constructed using lasso regression analysis through the PTC datasets of the Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT database. Finally, SDG were test in clinical PTC specimens and normal thyroid tissues. Results LASSO regression model was utilized to establish a novel FRG signature with 10 genes (ANGPTL7, CDKN2A, DPP4, DRD4, ISCU, PGD, SRXN1, TF, TFRC, TXNRD1) to predicts the prognosis of PTC, and the patients were separated into high-risk and low-risk groups by the risk score. The high-risk group had poorer survival than the low-risk group (p < 0.001). Receiver operating characteristic (ROC) curve analysis confirmed the signature's predictive capacity. Multivariate regression analysis identified the prognostic signature-based risk score was an independent prognostic indicator for PTC. The functional roles of the DEGs in the TGCA PTC cohort were explored using GO enrichment and KEGG pathway analyses. Immune related analysis demonstrated that the most types of immune cells and immunological function in the high-risk group were significant different with those in the low-risk group. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) verified the SDG have differences in expression between tumor tissue and normal thyroid tissue. In addition, cell experiments were conducted to observe the changes in cell morphology and expression of signature’s genes with the influence of ferroptosis induced by sorafenib. Conclusions We identified differently expressed FRG that may involve in PTC. A ferroptosis-related gene signature has significant values in predicting the patients’ prognoses and targeting ferroptosis may be an alternative for PTC’s therapy.


2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Wenkai Han ◽  
Xiaoyan Xu ◽  
Kai Che ◽  
Guofeng Ma ◽  
Danxia Li ◽  
...  

Background. Autophagy plays an essential role in tumorigenesis. At present, due to the unclear role of autophagy in renal clear cell carcinoma, we studied the potential value of autophagy-related genes (ARGs) in renal clear cell carcinoma (ccRCC). Methods. We obtained all ccRCC data from The Cancer Genome Atlas (TCGA). We extracted the expression data of ARGs for difference analysis and carried out biological function analysis on the different results. The autophagy risk model was constructed. The 5-year survival rate was assessed using the model, and the predictive power of the model was evaluated from multiple perspectives. Cox regression analysis was use to assess whether the model could be an independent prognostic factor. Finally, the correlation between the model and clinical indicators is analyzed. Results. The patients were divided into the high-risk group and low-risk group according to the median of autophagy risk score, and the results showed that the prognosis of the low-risk group was better than that of a high-risk group. The validation results of external data sets show that our model has good predictive value for ccRCC patients. The model can be an independent prognostic factor. Finally, the results show that our model has a stable predictive ability. Conclusion. The autophagy gene model we constructed can be used as an excellent prognostic indicator for ccRCC. Our study provides the possibility of individualized and precise treatment for ccRCC patients.


2020 ◽  
Author(s):  
Zhuolun Sun ◽  
Changying Jing ◽  
Chutian Xiao ◽  
Mingxiao Zhang ◽  
Zhenqing Wang ◽  
...  

Abstract Background: Kidney renal clear cell carcinoma (KIRC) is the most common and lethal renal cell carcinoma (RCC) histological subtype. Ferroptosis is a newly discovered programmed cell death and serves an essential role in tumor occurrence and development. The purpose of this study is to analyze ferroptosis-related gene (FRG) expression profiles and to construct a multi-gene signature for predicting the prognosis of KIRC patients.Methods:RNA-sequencing data and clinicopathological data of KIRC patients were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed FRGs between KIRC and normal tissues were identified using ‘limma’ package in R. GO and KEGG enrichment analyses were conducted to elucidate the biological functions and pathways of differentially expressed FRGs. Consensus clustering was used to investigate the relationship between the expression of FRGs and clinical phenotypes. Univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis were used to screen genes related to prognosis and construct the optimal signature. Then, a nomogram was established to predict individual survival probability by combining clinical features and prognostic signature.Results: A total of 19 differentially expressed FRGs were identified. Consensus clustering identified two clusters of KIRC patients with distinguished prognostic. Functional analysis revealed that metabolism-related pathways were enriched, especially lipid metabolism. A 7-gene ferroptosis-related prognostic signature was constructed to stratify the TCGA training cohort into high- and low-risk groups where the prognosis was significantly worse in the high-risk group. The signature was identified as an independent prognostic indicator for KIRC. These findings were validated in the testing cohort, the entire cohort, and the International Cancer Genome Consortium (ICGC) cohort. We further demonstrated that the signature-based risk score was highly associated with the KIRC progression. Further stratified survival analysis showed that the high-risk group had a significantly lower overall survival (OS) rate than those in the low-risk group. Moreover, we constructed a nomogram that had a strong ability to forecast the OS of the KIRC patients.Conclusion: We constructed a ferroptosis-related prognostic signature, which might provide a reliable prognosis assessment tool for clinician to guide clinical decision-making and outcomes research.


2021 ◽  
Author(s):  
Tian Lan ◽  
Die Wu ◽  
Wei Quan ◽  
Donghu Yu ◽  
Sheng Li ◽  
...  

Abstract Background: Glioma is a fatal brain tumor characterized by invasive nature, rapidly proliferation and tumor recurrence. Despite aggressive surgical resection followed by concurrent radiotherapy and chemotherapy, the overall survival (OS) of Glioma patients remains poor. Ferroptosis is a unique modality to regulate programmed cell death and associated with multiple steps of tumorigenesis of a variety of tumors.Methods: In this study, ferroptosis-related genes model was identified by differential analysis and Cox regression analysis. GO, KEGG and GSVA analysis were used to detect the potential biological functions and signaling pathway. The infiltration of immune cells was quantified by Cibersort.Results: The patients’ samples are stratified into two risk groups based on 4-gene signature. High-risk group has poorer overall survival. The results of functional analysis indicated that the extracellular matrix-related biologic functions and pathways were enriched in high-risk group, and that the infiltration of immunocytes is different in two groups.Conclusion: In summary, a novel ferroptosis-related gene signature can be used for prognostic prediction in glioma. The filtered genes related to ferroptosis in clinical could be a potential extra method to assess glioma patients’ prognosis and therapeutic.


2020 ◽  
Author(s):  
Zhuolun Sun ◽  
Changying Jing ◽  
Chutian Xiao ◽  
Mingxiao Zhang ◽  
Zhenqing Wang ◽  
...  

Abstract Background: Kidney renal clear cell carcinoma (KIRC) is the most common and lethal renal cell carcinoma (RCC) histological subtype. Ferroptosis is a newly discovered programmed cell death and serves an essential role in tumor occurrence and development. The purpose of this study is to analyze ferroptosis-related gene (FRG) expression profiles and to construct a multi-gene signature for predicting the prognosis of KIRC patients.Methods:RNA-sequencing data and clinicopathological data of KIRC patients were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed FRGs between KIRC and normal tissues were identified using ‘limma’ package in R. GO and KEGG enrichment analyses were conducted to elucidate the biological functions and pathways of differentially expressed FRGs. Consensus clustering was used to investigate the relationship between the expression of FRGs and clinical phenotypes. Univariate and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis were used to screen genes related to prognosis and construct the optimal signature. Then, a nomogram was established to predict individual survival probability by combining clinical features and prognostic signature.Results: A total of 19 differentially expressed FRGs were identified. Consensus clustering identified two clusters of KIRC patients with distinguished prognostic. Functional analysis revealed that metabolism-related pathways were enriched, especially lipid metabolism. A 7-gene ferroptosis-related prognostic signature was constructed to stratify the TCGA training cohort into high- and low-risk groups where the prognosis was significantly worse in the high-risk group. The signature was identified as an independent prognostic indicator for KIRC. These findings were validated in the testing cohort, the entire cohort, and the International Cancer Genome Consortium (ICGC) cohort. We further demonstrated that the signature-based risk score was highly associated with the KIRC progression. Further stratified survival analysis showed that the high-risk group had a significantly lower overall survival (OS) rate than those in the low-risk group. Moreover, we constructed a nomogram that had a strong ability to forecast the OS of the KIRC patients.Conclusion: We constructed a ferroptosis-related prognostic signature, which might provide a reliable prognosis assessment tool for clinician to guide clinical decision-making and outcomes research.


2022 ◽  
Author(s):  
Cong Zhang ◽  
Cailing Zeng ◽  
Shaoquan Xiong ◽  
Zewei Zhao ◽  
Guoyu Wu

Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease and one of the most common malignancies in the world. Previous studies have found that mitophagy plays an important role in the progression of colorectal cancer. This study is aimed to investigate the relationship between mitophagy-related genes and the prognosis of patients with CRC.Methods: Gene expression profiles and clinical information of CRC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) regression analysis were used to establish the prognostic signature composed of mitophagy related genes. Kaplan-Meier curve and receiver operating characteristic (ROC) curve were used to analyze patient survival and verify the predictive accuracy of the signature, respectively. Construction of a nomogram prognostic prediction model was based on risk scores and clinicopathological parameters. Using the Genomics of Drug Sensitivity in Cancer (GDSC) database and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to estimate the sensitivity of chemotherapy, targeted therapy and immunotherapy. Results: A total of 44 mitophagy-driven genes connected with CRC survival were identified, and prognostic signature was established based on the expression of 10 of them (AMBRA1, ATG14, MAP1LC3A, MAP1LC3B, OPTN, VDAC1, ATG5, CSNK2A2, MFN1, TOMM22). Patients were divided into high-risk and low-risk groups based on the median risk score, and the survival of patients in the high-risk group was significantly shorter than that of the low-risk group among the TCGA cohort (median OS 67.3 months vs not reached, p=0.00059) and two independent cohorts from GEO (median OS in GSE17536: 54.0 months vs not reached, p=0.0082; in GSE245: 7.7 months vs not reached, p=0.025). ROC curve showed that the area under the curves (AUC) of 1-, 3- and 5-year survival were 0.66, 0.66 and 0.64, respectively. Multivariate Cox regression analysis confirmed the independent prognostic value of the signature. Then we constructed a nomogram combining the risk score, age and M stage, which had a concordance index of survival prediction of 0.77 (95% CI=0.71-0.83) and more robust predictive sensitivity and specificity. Results showed that CD8+ T cells, regulatory T cells and activated NK cells were significantly more abundant in the high-risk group. Furthermore, patients in the high-risk group were more sensitive to potential targeted therapies, including Motesanib, ATRA, Olaparib, Selumetinib, AZD8055 and immunotherapy. Conclusion: In conclusion, we constructed and validated a novel mitophagy related gene signature that can be used as an independent prognostic biomarker for CRC, and may lead to better stratification and selection of precise treatment for CRC patients.


2021 ◽  
Vol 2021 ◽  
pp. 1-31
Author(s):  
Wenzheng Chen ◽  
Jianfeng Huang ◽  
Jianbo Xiong ◽  
Pengcheng Fu ◽  
Changyu Chen ◽  
...  

Background. The tumor microenvironment (TME) is associated with disease outcomes and treatment response in colon cancer. Here, we constructed a TME-related gene signature that is prognosis of disease survival and may predict response to immunotherapy in colon cancer. Methods. We calculated immune and stromal scores for 385 colon cancer samples from The Cancer Genome Atlas (TCGA) database using the ESTIMATE algorithm. We identified nine TME-related prognostic genes using Cox regression analysis. We evaluated associations between protein expression, extent of immune cell infiltrate, and patient survival. We calculated risk scores and built a clinical predictive model for the TME-related gene signature. Receiver operating characteristic (ROC) curves were generated to assess the predictive power of the signature. We estimated the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs in patients using the pRRophetic algorithm. The expression of immune checkpoint genes was evaluated. Results. High immune and stromal scores are significantly associated with poor overall survival ( p < 0.05 ). We identified 773 differential TME-related prognostic genes associated with survival; these genes were enriched in immune-related pathways. Nine key prognostic genes were identified and were used to construct a TME-related prognostic signature: CADM3, LEP, CD1B, PDE1B, CCL22, ABI3BP, IGLON5, SELE, and TGFB1. This signature identified a high-risk group with worse survival outcomes, based on Kaplan-Meier analysis. A nomogram composed of clinicopathological factors and risk score exhibited good accuracy. Drug sensitivity analysis identified no difference in sensitivity between the high-risk and low-risk groups. High-risk patients had higher expression of PD-1, PDL-1, and CTLA-4 and lower expression of LAG-3 and VSIR. Infiltration of dendritic cells was higher in the high-risk group. Conclusions. We identified a novel prognostic TME-related gene expression signature in colon cancer. Stratification of patients based on this gene signature could be used to improve outcomes and guide better therapy for colon cancer patients.


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