scholarly journals Establishment and Validation of a Prognostic Risk Model for Autophagy-Related Genes in Clear Cell Renal Cell Carcinoma

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.

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.


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.


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 ◽  
Vol 11 ◽  
Author(s):  
Zhuolun Sun ◽  
Changying Jing ◽  
Xudong Guo ◽  
Mingxiao Zhang ◽  
Feng Kong ◽  
...  

Kidney renal clear cell carcinoma (KIRC) has long been identified as a highly immune-infiltrated tumor. However, the underlying role of pyroptosis in the tumor microenvironment (TME) of KIRC remains poorly described. Herein, we systematically analyzed the prognostic value, role in the TME, response to ICIs, and drug sensitivity of pyroptosis-related genes (PRGs) in KIRC patients based on The Cancer Genome Atlas (TCGA) database. Cluster 2, by consensus clustering for 24 PRGs, presented a poor prognosis, likely because malignancy-related hallmarks were remarkably enriched. Additionally, we constructed a prognostic prediction model that discriminated well between high- and low-risk patients and was further confirmed in external E-MTAB-1980 cohort and HSP cohort. By further analyzing the TME based on the risk model, higher immune cell infiltration and lower tumor purity were found in the high-risk group, which presented a poor prognosis. Patients with high risk scores also exhibited higher ICI expression, indicating that these patients may be more prone to profit from ICIs. The sensitivity to anticancer drugs that correlated with model-related genes was also identified. Collectively, the pyroptosis-related prognosis risk model may improve prognostic information and provide directions for current research investigations on immunotherapeutic strategies for KIRC patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Junwan Lu ◽  
Changrui Qian ◽  
Yongan Ji ◽  
Qiyu Bao ◽  
Bin Lu

Bromodomain (BRD) proteins exhibit a variety of activities, such as histone modification, transcription factor recruitment, chromatin remodeling, and mediator or enhancer complex assembly, that affect transcription initiation and elongation. These proteins also participate in epigenetic regulation. Although specific epigenetic regulation plays an important role in the occurrence and development of cancer, the characteristics of the BRD family in renal clear cell carcinoma (KIRC) have not been determined. In this study, we investigated the expression of BRD family genes in KIRC at the transcriptome level and examined the relationship of the expression of these genes with patient overall survival. mRNA levels of tumor tissues and adjacent tissues were extracted from The Cancer Genome Atlas (TCGA) database. Seven BRD genes (KAT2A, KAT2B, SP140, BRD9, BRPF3, SMARCA2, and EP300) were searched by using LASSO Cox regression and the model with prognostic risk integration. The patients were divided into two groups: high risk and low risk. The combined analysis of these seven BRD genes showed a significant association with the high-risk groups and lower overall survival (OS). This analysis demonstrated that total survival could be predicted well in the low-risk group according to the time-dependent receiver operating characteristic (ROC) curve. The prognosis was determined to be consistent with that obtained using an independent dataset from TCGA. The relevant biological functions were identified using Gene Set Enrichment Analysis (GSEA). In summary, this study provides an optimized survival prediction model and promising data resources for further research investigating the role of the expression of BRD genes in KIRC.


2021 ◽  
Author(s):  
Guodong Fang ◽  
Xudan Wang

Abstract Tumor immunotherapy has become one of the hotspot methods of tumor treatment. This study aims to screen and analyze the role of prognostic genes in the diagnosis, prognosis and immunotherapy of clear cell renal cell carcinoma (ccRCC) by bioinformatics methods. Based on the Gene Expression Omnibus Datasets and The Cancer Genome Atlas (TCGA) Datasets, we screened out the nine differentially expressed genes (TYROBP, APOC1, CSTA, LY96, LAPTM5, CD300A, ALOX5, C1QA, C1QB) associated with clinical traits and prognosis by "WGCNA" package in R and Kaplan-Meier Plotter. The ROC curves showed that the combination of these genes had high diagnostic value (AUC=0.990). The COX regression analysis was used to construct the risk signature, and the risk score calculated by the 9 genes was an independent prognostic factor that could predict survival probability for patients at 1 year, 3 years, 5 years. The high-risk group had lower Tumor Immune Dysfunction and Exclusion score and higher tumor mutation burden and PD-1 levels. The immune checkpoint blockade response rates in the high- and low- risk groups were 49.25% and 24.72% (p≤0.001). The immune infiltration and Pearson correlation analyses suggested that the prognostic genes were negatively correlated with activated dendritic cells in the low-risk group, rather than in the high-risk group. In conclusion, prognostic-related genes have high diagnostic value and can guide prognostic evaluation and immunotherapy for ccRCC, and this process needs to be mediated by the activated dendritic cells.


2022 ◽  
Author(s):  
Fu Liu ◽  
Xinyuan Li ◽  
Xiang Zhou ◽  
Hang Tong ◽  
Xin Gou

Abstract Background: Renal cell carcinoma is the most common aggressive tumor of the genitourinary system. The main pathological subtype is clear cell renal cell carcinoma (ccRCC), and its treatment options are very limited. Therefore, identifying specific markers of renal clear cell carcinoma is of great significance for diagnosis and prognosis.Methods: From the TCGA database, we obtained information on 611 patients with renal clear cell carcinoma to analyze the relationship between hypoxia-related lncRNAs and overall survival. According to the coexpression of hypoxia genes and lncRNAs, genes related to hypoxia were identified. Difference analysis and Cox regression analysis were applied to assess survival-related risk factors. According to the median risk score of hypoxia-related genes, patients were divided into high-risk and low-risk groups. According to these gene characteristics and clinical parameters, a nomogram map was built, and GSEA was used for gene function annotation. RT-qRCR, Western Blot and Flow Cytometry were used to determine the role of SNHG19 in RCC cells.Results: By analyzing the coexpression of hypoxia genes and lncRNAs, 310 hypoxia-related genes were obtained. Six sHRlncRs were significantly correlated with the clinical outcomes of patients with ccRCC. Four sHRlncRs (AC011445.2, PTOV1-AS2, AP004609.3, and SNHG19) with the highest prognostic values were included in the group to construct the HRRS model. The high-risk group had a shorter OS than the low-risk group. HR-lncRNAs were considered to be an independent prognostic factor and associated with OS. The high- and low-risk groups showed different pathways in GSEA. Experiments showed that SNHG19 plays essential roles in autophagy and apoptosis of RCC cells.Conclusion: Our research shows that we established and verified a hypoxia-related lncRNA model that accurately correlates with ccRCC patients. This study also provides novel insights into hypoxia-based mechanisms and provides new biomarkers for the poor prognosis of ccRCC patients.


2020 ◽  
Author(s):  
Yuanbin Jiang ◽  
Xin Gou ◽  
Zongjie Wei ◽  
Jianyu Tan ◽  
Haitao Yu ◽  
...  

Abstract Background: Renal cell carcinoma (RCC) is one of the most common aggressive malignant tumors in urogenital system, and the clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinoma. Immune related long non-coding RNAs (IRlncRs) plentiful in immune cells and immune microenvironment (IME) are potential in evaluating prognosis and assessing the effects of immunotherapy. A completed and meaningful IRlncRs analysis based on abundant ccRCC gene samples from The Cancer Genome Atlas (TCGA) will provide insight in this field. Methods: Based on the TCGA dataset, we integrated the expression profiles of IRlncRs and overall survival (OS) in the 611 ccRCC patients. The immune score of each sample was calculated based on the expression level of immune-related genes and used to identify the most meaningful IRlncRs. Survival-related IRlncRs (sIRlncRs) was estimated by calculating the algorithm of difference and COX regression analysis in ccRCC patients. Based on the median immune-related risk score (IRRS) developed from the screened sIRlncRs, the high-risk and low-risk components were distinguished. Functional annotation was detected by gene set enrichment analysis (GSEA) and principal component analysis (PCA), and the immune composition and purity of the tumor was evaluated by microenvironment cell population records. The expression levels of three sIRlncRs were verified in various tissues and cell lines.Results: A total of 39 IRlncRs were collected by Pearson correlation analyses among immune score and the lncRNA expression. A total of 7 sIRlncRs were significantly associated with the clinical outcomes of ccRCC patients. Three sIRlncRs (ATP1A1-AS1, IL10RB-DT and MELTF-AS1) with the most significant prognostic values were enrolled to build the IRRS model in which the OS of in the high-risk group was shorter than that in the low-risk group. The IRRS was identified as an independent prognosis factor and correlated with the OS. The high-risk group and low-risk group illustrated different distributions in PCA and different immune status in GSEA. Besides, we found the more significant expression in certain ccRCC cell lines and tumor tissues of ccRCC patients compared with the HK-2 and adjacent tissues respectively. Additionally, the expression levels of lncR-MELTF-AS1 and IL10RB-DT were remarkably enhanced along the more advanced T-stages, but the lncR-ATP1A1-AS1 showed the inverse gradient.Conclusion: Our results demonstrate some sIRlncRs with remark clinical relevance show the latent monitoring and prognosis values for ccRCC patients and may provide new insight in immunological researches and treatment strategies of ccRCC patients.


2020 ◽  
Author(s):  
Xiang Zhou ◽  
Xin Gou ◽  
Zongjie Wei ◽  
Jianyu Tan ◽  
Haitao Yu ◽  
...  

Abstract Background: Immune related long non-coding RNAs (IRlncRs) plentiful in immune cells and immune microenvironment (IME) are potential in evaluating prognosis and assessing the effects of immunotherapy. A complete and meaningful IRlncRs analysis based on abundant clear cell renal cell carcinoma (ccRCC) gene samples from The Cancer Genome Atlas (TCGA) will provide insight in this field. Methods: Based on the TCGA dataset, we integrated the expression profiles of IRlncRs and overall survival (OS) in the 611 ccRCC patients. The immune score of each sample was calculated based on the expression level of immune-related genes and used to identify the most meaningful IRlncRs. Survival-related IRlncRs (sIRlncRs) was estimated by calculating the algorithm of difference and COX regression analysis in ccRCC patients. Based on the median immune-related risk score (IRRS) developed from the screened sIRlncRs, the high-risk and low-risk components were distinguished. Functional annotation was detected by gene set enrichment analysis (GSEA) and principal component analysis (PCA), and the immune composition and purity of the tumor was evaluated by microenvironment cell population records. The expression levels of three sIRlncRs were verified in various tissues and cell lines. Results: A total of 39 IRlncRs were collected by Pearson correlation analyses among immune score and the lncRNA expression. A total of 7 sIRlncRs were significantly associated with the clinical outcomes of ccRCC patients. Three sIRlncRs (ATP1A1-AS1, IL10RB-DT and MELTF-AS1) with the most significant prognostic values were enrolled to build the IRRS model in which the OS of in the high-risk group was shorter than that in the low-risk group. The IRRS was identified as an independent prognosis factor and correlated with the OS. The high-risk group and low-risk group illustrated different distributions in PCA and different immune status in GSEA. Besides, we found the more significant expression in certain ccRCC cell lines and tumor tissues of ccRCC patients compared with the HK-2 and adjacent tissues respectively. Additionally, the expression levels of lncR-MELTF-AS1 and IL10RB-DT were remarkably enhanced along the more advanced T-stages, but the lncR-ATP1A1-AS1 showed the inverse gradient. Conclusion: Our results demonstrated some sIRlncRs with remark clinical relevance shown the latent monitoring and prognosis value of ccRCC patients and may provide new insight for immunological research and treatment strategies in ccRCC patients.


2021 ◽  
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.


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