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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