A Novel m6A Gene Signature Associated With Regulatory Immune Function for Prognosis Prediction in Clear-Cell Renal Cell Carcinoma

The important role of N6-methyladenosine (m6A) RNA methylation regulator in carcinogenesis and progression of clear-cell renal cell carcinoma (ccRCC) is poorly understood by now. In this study, we performed comprehensive analyses of m6A RNA methylation regulators in 975 ccRCC samples and 332 adjacent normal tissues and identified ccRCC-related m6A regulators. Moreover, the m6A diagnostic score based on ccRCC-related m6A regulators could accurately distinguish ccRCC from normal tissue in the Meta-cohort, which was further validated in the independent GSE-cohort and The Cancer Genome Atlas-cohort, with an area under the curve of 0.924, 0.867, and 0.795, respectively. Effective survival prediction of ccRCC by m6A risk score was also identified in the Cancer Genome Atlas training cohort and verified in the testing cohort and the independent GSE22541 cohort, with hazard ratio values of 3.474, 1.679, and 2.101 in the survival prognosis, respectively. The m6A risk score was identified as a risk factor of overall survival in ccRCC patients by the univariate Cox regression analysis, which was further verified in both the training cohort and the independent validation cohort. The integrated nomogram combining m6A risk score and predictable clinicopathologic factors could accurately predict the survival status of the ccRCC patients, with an area under the curve values of 85.2, 82.4, and 78.3% for the overall survival prediction in 1-, 3- and 5-year, respectively. Weighted gene co-expression network analysis with functional enrichment analysis indicated that m6A RNA methylation might affect clinical prognosis through regulating immune functions in patients with ccRCC.

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Ferroptosis-Related Gene-Based Prognostic Model and Immune Infiltration in Clear Cell Renal Cell Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.650416 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guo-Jiang Zhao ◽

Zonglong Wu ◽

Liyuan Ge ◽

Feilong Yang ◽

Kai Hong ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Risk Score ◽

Renal Cell ◽

Clear Cell ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cancer Genome Atlas ◽

Score Model ◽

Genome Atlas

Clear cell renal cell carcinoma (ccRCC) is one of the most common tumors in the urinary system. Ferroptosis plays a vital role in ccRCC development and progression. We did an update of ferroptosis-related multigene expression signature for individualized prognosis prediction in patients with ccRCC. Differentially expressed ferroptosis-related genes in ccRCC and normal samples were screened using The Cancer Genome Atlas. Univariate and multivariate Cox regression analyses and machine learning methods were employed to identify optimal prognosis-related genes. CARS1, CD44, FANCD2, HMGCR, NCOA4, SLC7A11, and ACACA were selected to establish a prognostic risk score model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these genes were mainly enriched in immune-related pathways; single-sample Gene Set Enrichment Analysis revealed several immune cells potentially related to ferroptosis. Kaplan–Meier survival analysis demonstrated that patients with high-risk scores had significantly poor overall survival (log-rank P = 7.815 × 10–11). The ferroptosis signature was identified as an independent prognostic factor. Finally, a prognostic nomogram, including the ferroptosis signature, age, histological grade, and stage status, was constructed. Analysis of The Cancer Genome Atlas-based calibration plots, C-index, and decision curve indicated the excellent predictive performance of the nomogram. The ferroptosis-related seven-gene risk score model is useful as a prognostic biomarker and suggests therapeutic targets for ccRCC. The prognostic nomogram may assist in individualized survival prediction and improve treatment strategies.

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Association of mutations in chromatin modifiers with poor survival in clear cell renal cell carcinoma: Analysis of the Cancer Genome Atlas Project.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.360 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 360-360 ◽

Cited By ~ 1

Author(s):

A. Ari Hakimi ◽

Irina Ostrovnaya ◽

Martin Henner Voss ◽

Robert John Motzer ◽

Paul Russo ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Competing Risk ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cancer Specific Survival ◽

Epigenetic Modifiers ◽

Cancer Genome Atlas ◽

Genome Atlas

360 Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p<0.0001 HR 4.03 [2.1-7.9]). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusions: BAP1, SETD2 and KDM5C mutations are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.

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A Novel Prognostic Model for Clear Cell Renal Cell Carcinoma with Differentially Expressed Immune-related lncRNA Pairs Based on the Cancer Genome Atlas

10.21203/rs.3.rs-728356/v1 ◽

2021 ◽

Author(s):

Chen Zhao ◽

Kewei Xiong ◽

Fengming Liu ◽

Xiangpan Li

Keyword(s):

Renal Cell Carcinoma ◽

Renal Cell ◽

Prognostic Model ◽

Cox Regression ◽

Clear Cell ◽

Risk Group ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cancer Genome Atlas ◽

Genome Atlas

Abstract Objective: To construct a novel prognostic model of immune-related lncRNA (irlncRNA) pairs in clear cell renal cell carcinoma (ccRCC). Methods: RNA-seq and clinical data were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed irlncRNAs (DEirlncRNAs) were obtained by co-expression strategy with immune genes. A 0-1 matrix was constructed according to DEirlncRNAs relevant expression levels. Univariate cox regression was used to select potential target pairs. Lasso regression with cross validation and multivariate cox regression were carried out to extract the final biomarker pairs for risk score calculation. Through calculating the optimal cutoff of AUCs, patients were divided into high and low risk group. Model validation was conducted by independent prognostic analysis, survival analysis, tumor-infiltrating and chemosensitivity analysis. Results: A total of 42 DEirlncRNAs were identified and 12 target pairs were included to construct the final model. The risk score were both significantly different according to univariate (p<0.001, HR=1.391, 95%CI [1.313–1.475]) and multivariate cox regression (p<0.001, HR=1.3104, 95%CI [1.227-1.399]). The AUC reached 0.765 at 1-year, 0.724 at 3-year and 0.785 at 5-year. Patients in the high-risk group had significantly poor survival, higher level of CD8+T infiltration, lower drug sensitivity of sunitinib and temsirolimus but higher sensitivity of lapatinib and pazopanib.Conclusion: The novel prognostic model constructed by paring irlncRNAs showed an effective clinical prediction in ccRCC patients.

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The long noncoding RNA urothelial carcinoma-associated 1 overexpression as a poor prognostic biomarker in clear cell renal cell carcinoma

Tumor Biology ◽

10.1177/1010428317698377 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831769837 ◽

Cited By ~ 1

Author(s):

Yang Wang ◽

Wen Gao ◽

Jiali Xu ◽

Yizhi Zhu ◽

Lingxiang Liu

Keyword(s):

Renal Cell Carcinoma ◽

Urothelial Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Noncoding Rna ◽

Clear Cell ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cancer Genome Atlas ◽

Genome Atlas

Long noncoding RNA urothelial carcinoma-associated 1 has previously played important roles in cancer. However, its role is still unknown in clear cell renal cell carcinoma. We utilized the most recent molecular and clinical data of clear cell renal cell carcinoma from The Cancer Genome Atlas project, and the relationship between urothelial carcinoma-associated 1 expression and the clinicopathological features was analyzed. Our results indicated that urothelial carcinoma-associated 1 overexpression was associated with male ( p = 0.003), wild-type PBRM1 ( p = 0.021), and BAP1 mutation ( p = 0.022) in clear cell renal cell carcinoma, although lower expression was found in tumors compared with normal controls, validated in tumor tissues from The Cancer Genome Atlas and 21 clear cell renal cell carcinoma patients at our hospital. Moreover, urothelial carcinoma-associated 1 overexpression indicated poor prognosis independently (Hazard Ratio [HR]: 1.92, p = 0.000) in clear cell renal cell carcinoma; it might be a potential detrimental gene considered as a predictive biomarker involved in clear cell renal cell carcinoma.

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Caspase 4 Overexpression in Clear Cell Renal Cell Carcinoma and Its Prognostic Role

10.21203/rs.3.rs-35104/v1 ◽

2020 ◽

Author(s):

Lingfeng Meng ◽

Zijian Tian ◽

Xingbo Long ◽

Tongxiang Diao ◽

Maolin Hu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Normal Tissues ◽

Kaplan Meier ◽

Cancer Genome Atlas ◽

Genome Atlas

Abstract Background: Caspase 4 (CASP4) dysregulation is related to the occurrence, development, and outcome of many malignant tumors, but its role in clear cell renal cell carcinoma (ccRCC) is unclear. This study was conducted to investigate the expression level of CASP4 in tumor tissues and its relationship with clinical prognosis of patients with ccRCC. Methods: First, the Oncomine and The Cancer Genome Atlas databases were used to determine CASP4 mRNA expression in ccRCC and its association with ccRCC prognosis. We then performed immunohistochemical staining and evaluation of 30 paired ccRCC and adjacent normal tissues to confirm these results. The correlation between CASP4 expression and ccRCC prognosis was evaluated using Kaplan-Meier analysis, and related genes and pathways were obtained from The Cancer Genome Atlas database by gene set enrichment analysis and gene set variation analysis. Finally, we explored the co-expression of genes with CASP4 in ccRCC. Results: CASP4 mRNA expression in ccRCC was significantly higher than that in normal tissues (p < 0.001). Kaplan-Meier analysis showed that the overall survival of patients with ccRCC showing high CASP4 expression was significantly reduced (p < 0.001). We then used external datasets (Gene Expression Omnibus database and patients from our center) to verify the level of CASP4 expression and survival differences (all p < 0.05). We also found that differential expression levels of CASP4 were correlated with pathological grade and clinical TNM stage (all p < 0.05). Conclusions: Overall, our study shows that CASP4 is highly expressed in ccRCC and is an important factor affecting prognosis. Thus, CASP4 may be a potential prognostic biomarker of ccRCC.

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BAP1 is overexpressed in black compared with white patients with Mx-M1 clear cell renal cell carcinoma: A report from the cancer genome atlas

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2015.12.019 ◽

2016 ◽

Vol 34 (6) ◽

pp. 259.e9-259.e14 ◽

Cited By ~ 3

Author(s):

David J. Paulucci ◽

John P. Sfakianos ◽

Shalini Singh Yadav ◽

Ketan K. Badani

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cancer Genome Atlas ◽

Genome Atlas ◽

White Patients

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CpG-methylation-based risk score predicts progression in colorectal cancer

Epigenomics ◽

10.2217/epi-2019-0300 ◽

2020 ◽

Vol 12 (7) ◽

pp. 605-615 ◽

Cited By ~ 2

Author(s):

Yao Deng ◽

Hao Wan ◽

Jianbo Tian ◽

Xiang Cheng ◽

Meilin Rao ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Area Under The Curve ◽

The Cancer Genome Atlas ◽

Free Interval ◽

Future Clinical Practice ◽

Risk Of Progression ◽

Precision Therapy ◽

Cancer Genome Atlas ◽

Genome Atlas

Aim: To identify patients with colorectal cancer (CRC) who are at a truly higher risk of progression, which is key for individualized approaches to precision therapy. Materials & methods: We developed a predictor associated with progression-free interval (PFI) using The Cancer Genome Atlas CRC methylation data. Results: The risk score was associated with PFI in the whole cohort (p < 0.001). A nomogram consisting of the risk score and other significant clinical features was generated to predict the 3- and 5-year PFI in the whole set (area under the curve: 0.79 and 0.71, respectively). Conclusion: The risk score based on 23 DNA-methylation sites may serve as the basis for improved prediction of progression in patients with CRC in future clinical practice.

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The Early Diagnostic and Prognostic Value of BIRC5 in Clear-Cell Renal Cell Carcinoma Based on the Cancer Genome Atlas Data

Urologia Internationalis ◽

10.1159/000517310 ◽

2021 ◽

pp. 1-8

Author(s):

Jingyuan Wang ◽

Min Chen ◽

Chengxue Dang ◽

Hao Zhang ◽

Xin Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Early Diagnosis ◽

Renal Cell ◽

Clear Cell ◽

The Cancer Genome Atlas ◽

Clinicopathological Parameters ◽

Normal Kidney ◽

Cell Renal Cell Carcinoma ◽

Cancer Genome Atlas ◽

Genome Atlas

Purpose: The aim of this study was to investigate the role of BIRC5 for early diagnosis and prognosis in clear-cell renal cell carcinoma (ccRCC) by studying the expression of BIRC5 and the correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC. Methods: The BIRC5 expression in ccRCC tissues and normal kidney tissues was measured using the Cancer Genome Atlas database and the Human Protein Atlas database. The correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC was analyzed using UALCAN, the Kaplan-Meier plotter, GEPIA, and SurvExpress. Thirteen-paired ccRCC plasma samples were used to verify the BIRC5 early diagnosis value of ccRCC. Results: The BIRC5 expression is significantly higher in ccRCC than in normal kidney tissues, and is correlated with the clinical stage and pathological grade of ccRCC (p < 0.05). The result of analyzing the relationship between BIRC5 expression and outcomes in ccRCC indicates that a high BIRC5 expression is an independent prognostic factor affecting the overall survival and disease-free survival of ccRCC (p < 0.05). Compared with normal kidney tissues, the immunohistochemical test shows that BIRC5 is significantly upregulated in ccRCC tissues. mRNA expression levels of BIRC5 were significantly higher in the ccRCC plasma than normal (p < 0.05). Conclusions: The high expression of BIRC5 is an important indicator for the prognosis of ccRCC, which makes BIRC5 an effective biomarker for predicting the prognosis of patients in ccRCC. BIRC5 may be a great potential biomarker for early diagnosis of ccRCC.

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Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining

Frontiers in Genetics ◽

10.3389/fgene.2020.600248 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lingfeng Meng ◽

Zijian Tian ◽

Xingbo Long ◽

Tongxiang Diao ◽

Maolin Hu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Renal Cell ◽

Drug Sensitivity ◽

Clear Cell ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Normal Tissues ◽

Disease Prognosis ◽

Cancer Genome Atlas ◽

Genome Atlas

The dysregulation of caspase 4 (CASP4) expression is related to the occurrence, development, and outcome of many malignant tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Herein, we investigated the expression of CASP4 in tumor tissues and its relationship with clinical prognosis, immune infiltration, and drug sensitivity status of ccRCC patients. Oncomine and The Cancer Genome Atlas (TCGA) databases were used to determine CASP4 mRNA expression in ccRCC patients. The correlation between CASP4 expression and disease prognosis was evaluated using Kaplan–Meier analysis. Related pathways were obtained from TCGA database via gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). Meanwhile, genes co-expressing with CASP4 in ccRCC were investigated. Finally, we analyzed the proportion of tumor-infiltrating immune cells (TICs) using the CIBERSORT computational method and assessed CASP4 methylation and its relationship with drug sensitivity. Immunohistochemical analysis of 30 paired ccRCC and adjacent normal tissues confirmed the in silico results. CASP4 mRNA expression in ccRCC was significantly higher than that in the normal tissues, positively correlated with clinicopathological features (clinical stage and pathological grade), and negatively correlated with patient overall survival (OS). GSEA and GSVA showed that the genes in the CASP4-high expression group were primarily enriched in immune-related activities. Moreover, CIBERSORT analysis of TIC proportions revealed that activated CD4 memory T cells were positively correlated with CASP4 expression. Notably, methylation analysis revealed that the abnormal upregulation of CASP4 might be caused by hypomethylation. Finally, we found that the abnormal expression of CASP4 may be related to tumor drug resistance. Overall, our study shows that CASP4 is overexpressed in ccRCC and is an important factor affecting disease prognosis. Hence, CASP4 may serve as a potential prognostic biomarker and therapeutic target in ccRCC.

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