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

ABSTRACT: 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.

SUBMITTER: Zhao GJ

PROVIDER: S-EPMC8220217 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSince its discovery, clear cell renal cell carcinoma (ccRCC) has been the most prevalent and lethal kidney malignancy. Our research aims to identify possible prognostic genes of ccRCC and to develop efficient prognostic models for ccRCC patients based on multi-omics investigations to shed light on the treatment and prognosis of ccRCC.MethodsTo determine a risk score for each patient, we screened out differentially expressed genes using data from tumor samples, and control samples mined from The Cancer Genome Atlas (TCGA) and GTEx datasets. Somatic mutation and copy number variation profiles were analyzed to look for specific genomic changes connected to risk scores. To investigate potential functional relationships of prognostic genes, gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were carried out. We created a prognostic model by fusing risk ratings with other clinical variables. For validation, the 786-O cell line was used to carry out the dual-gRNA approach to knock down CAPN12 and MSC. This was followed by qRT-PCR to verify the knockdown of CAPN12 and MSC.ResultsFor ccRCC, seven predictive genes were discovered: PVT1, MSC, ALDH6A1, TRIB3, QRFPR, CYS1, and CAPN12. The most enriched pathways in the GSVA study and GSEA analysis promote tumorigenesis and immune system modulation. The risk score derived from prognostic genes corresponds with immune infiltration cells and helps predict how well a medicine will work. The mutation of numerous oncogenes was also linked to a high-risk score. A prognostic model with a high ROC value was created for the risk score. An in vitro study demonstrates that the suppression of CAPN12 and MSC dramatically reduced the ability of 786-O cells to proliferate in the CCK-8 proliferation assay and plate clonality assays.ConclusionsA thorough prognostic model with good performance has been developed for ccRCC patients using seven prognostic genes that were discovered to be related to ccRCC prognosis. In ccRCC, CAPN12 and MSC were significant indicators and would make good therapeutic targets.

Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). Anoikis plays an essential function in tumourigenesis, whereas the role of anoikis in ccRCC remains unclear. Methods: Anoikis-related genes (ARGs) were collected from the MSigDB database. According to univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized to select the ARGs associated with the overall rate (OS). Multivariate Cox regression analysis was conducted to identify 5 prognostic ARGs, and a risk model was established. The Kaplan-Meier survival analysis was used to evaluate the OS rate of ccRCC patients. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Gene set enrichment analysis (GSVA) were utilized to investigate the molecular mechanism of patients in the low- and high-risk group. ESTIMATE, CIBERSOT, and single sample gene set enrichment analysis (ssGSEA) algorithms were conducted to estimate the immune infiltration landscape. Consensus clustering analysis was performed to divide the patients into different subgroups. Results: A fresh risk model was constructed based on the 5 prognostic ARGs (CHEK2, PDK4, ZNF304, SNAI2, SRC). The Kaplan-Meier survival analysis indicated that the OS rate of patients with a low-risk score was significantly higher than those with a high-risk score. Consensus clustering analysis successfully clustered the patients into two subgroups, with a remarkable difference in immune infiltration landscape and prognosis. The ESTIMATE, CIBERSORT, and ssGSEA results illustrated a significant gap in immune infiltration landscape of patients in the low- and high-risk group. Enrichment analysis and GSVA revealed that immune-related signaling pathways might mediate the role of ARGs in ccRCC. The nomogram results illustrated that the ARGs prognostic signature was an independent prognostic predictor that distinguished it from other clinical characteristics. TIDE score showed a promising immunotherapy response of ccRCC patients in different risk subgroups and cluster subgroups. Conclusion: Our study revealed that ARGs play a carcinogenic role in ccRCC. Additionally, we firstly integrated multiple ARGs to establish a risk-predictive model. This study highlights that ARGs could be implemented as a stratification factor for individualized and precise treatment in ccRCC patients.

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

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