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Profiles of overall survival-related gene expression-based risk signature and their prognostic implications in clear cell renal cell carcinoma.

ABSTRACT: The present work aimed to evaluate the prognostic value of overall survival (OS)-related genes in clear cell renal cell carcinoma (ccRCC) and to develop a nomogram for clinical use. Transcriptome data from The Cancer Genome Atlas (TCGA) were collected to screen differentially expressed genes (DEGs) between ccRCC patients with OS > 5 years (149 patients) and those with <1 year (52 patients). In TCGA training set (265 patients), seven DEGs (cytochrome P450 family 3 subfamily A member 7 (CYP3A7), contactin-associated protein family member 5 (CNTNAP5), adenylate cyclase 2 (ADCY2), TOX high mobility group box family member 3 (TOX3), plasminogen (PLG), enamelin (ENAM), and collagen type VII ? 1 chain (COL7A1)) were further selected to build a prognostic risk signature by the least absolute shrinkage and selection operator (LASSO) Cox regression model. Survival analysis confirmed that the OS in the high-risk group was dramatically shorter than their low-risk counterparts. Next, univariate and multivariate Cox regression revealed the seven genes-based risk score, age, and Tumor, lymph Node, and Metastasis staging system (TNM) stage were independent prognostic factors to OS, based on which a novel nomogram was constructed and validated in both TCGA validation set (265 patients) and the International Cancer Genome Consortium cohort (ICGC, 84 patients). A decent predictive performance of the nomogram was observed, the C-indices and corresponding 95% confidence intervals of TCGA training set, validation set, and ICGC cohort were 0.78 (0.74-0.82), 0.75 (0.70-0.80), and 0.70 (0.60-0.80), respectively. Moreover, the calibration plots of 3- and 5 years survival probability indicated favorable curve-fitting performance in the above three groups. In conclusion, the proposed seven genes signature-based nomogram is a promising and robust tool for predicting the OS of ccRCC, which may help tailor individualized therapeutic strategies.

SUBMITTER: He Z

PROVIDER: S-EPMC7494988 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Profiles of overall survival-related gene expression-based risk signature and their prognostic implications in clear cell renal cell carcinoma.

He Zihao Z Deng Tuo T Duan Xiaolu X Zeng Guohua G

Bioscience reports 20200901 9

The present work aimed to evaluate the prognostic value of overall survival (OS)-related genes in clear cell renal cell carcinoma (ccRCC) and to develop a nomogram for clinical use. Transcriptome data from The Cancer Genome Atlas (TCGA) were collected to screen differentially expressed genes (DEGs) between ccRCC patients with OS > 5 years (149 patients) and those with <1 year (52 patients). In TCGA training set (265 patients), seven DEGs (cytochrome P450 family 3 subfamily A member 7 (CYP3A7), c ...[more]

PMID: 32789468

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Project description:BackgroundKidney cancer, especially clear cell renal cell carcinoma (ccRCC), is one of the most common cancers in the urinary system. Previous studies suggested that certain members of MUCINs could serve as independent predictors for the survival of ccRCC patients. None of them, however, is robust enough to predict prognosis accurately.ObjectiveTo analyze the correlation of MUCINs alterations and their expression levels with the prognosis of ccRCC patients and develop a prognosis-related predictor.MethodsWe applied whole-exome sequencing in samples from 22 Chinese ccRCC patients to identify genetic alterations in MUCIN genes and analyzed their genetic alterations, expression, and correlation with survival using the TCGA, GSE73731, and GSE29069 datasets.ResultGenetic alternations in MUCINs were identified in 91% and 51% of ccRCC patients in our cohort and the TCGA database, respectively. No correlation with survival was found for the genetic alterations. Using unsupervised clustering analysis of gene expression, we identified two major clusters of MUCIN expression patterns. Cluster 1 was characterized by a global overexpression of MUC1, MUC12, MUC13, MUC16, and OVGP1; and cluster 2 was characterized by a global overexpression of MUC4, MUC5B, MUC6, MUC20, EMCN, and MCAM. Patients with cluster 1 expression pattern had significantly shorter overall survival time and worse clinical features, including higher tumor grades and metastasis. Meanwhile, they had a higher level of mutation counts and more infiltrated immune cells, but lower enrichment in angiogenesis signature genes. A five-MUCINs expression signature was constructed from cluster 1, and notably, it was demonstrated to be associated with shorter overall survival. A similar worse clinical feature, lower angiogenesis but the more immune signature, was identified in samples presented with signature 1. In the validation data set GSE29069, patients with signature 1 were also associated with a trend of poor survival outcomes.ConclusionWe established a five-MUCINs expression signature as a new prognostic marker for ccRCC. The distinct tumor microenvironment feature between the two signatures may further affect ccRCC patients' clinical management.

Project description:BackgroundFerredoxin 1 (FDX1) is a newly discovered gene regulating cuprotosis. However, the effect of FDX1 expression on clear renal cell carcinoma (ccRCC) is unknown.MethodsGene expression profiles and clinical data of ccRCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The differences in FDX1 expression between ccRCC and nonneoplastic tissues adjacent to cancer were analyzed by R software. The results were validated by GEO data, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), and immunohistochemistry (IHC). Chi-square test was used to analyze the clinical pathological parameters. Kaplan-Meier survival analysis and Cox proportional hazard regression model selection were used to evaluate the effect of FDX1 expression on overall survival. Protein interaction networks were used to analyze other proteins that interact with FDX1. Signal pathway analysis was performed for possible FDX1 enrichment using GSEA and ssGSEA algorithms. Pan-cancer analysis of FDX1 was carried out through TCGA database.ResultsThe FDX1 expression in nontumor tissues was significantly higher than that in ccRCC, and the expression difference was verified by GEO data, qRT-PCR, WB, and IHC. The high expression of FDX1 was significantly related to the well overall survival rate (P < 0.05). The chi-square test showed that the high expression of FDX1 was related to gender, TNM stage, T stage, lymph node metastasis, and pathological grade. Additionally, the FDX1 expression level was different in groups classified based on pathological grade, gender, TNM stage, T stage, lymph node metastasis, and distant metastasis (P < 0.05). The multivariate analysis revealed the high expression of FDX1 as an important independent predictor for overall survival. STRING database results showed that LIAS and LIPT1 may interact with FDX1 in the PPI network, which are also involved in the regulation of cuprotosis. The GSEA and ssGSEA results showed that the FDX1 was enriched in the anticancer pathway. The FDX1 high expression is associated with better prognosis in many cancers, as revealed by pan-cancer analysis.ConclusionFDX1 may play a role in the progression of ccRCC as a tumor suppressor gene. It can be used as a potential prognostic indicator and therapeutic target of ccRCC. However, the cuprotosis regulatory role in the development of ccRCC needs to be further verified.

Dataset Information

Profiles of overall survival-related gene expression-based risk signature and their prognostic implications in clear cell renal cell carcinoma.

Publications

Profiles of overall survival-related gene expression-based risk signature and their prognostic implications in clear cell renal cell carcinoma.

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