Construction and validation of programmed cell death-based molecular clusters for prognostic and therapeutic significance of clear cell renal cell carcinoma

As the dominant histological subtype of kidney cancer, clear cell renal cell carcinoma (ccRCC) poorly responds to conventional chemotherapy and radiotherapy. Although novel immunother-apies such as immune checkpoint inhibitors could have a durable effect in treating ccRCC pa-tients, the limited availability of dependable biomarkers has restricted their application in clinic. In the study of carcinogenesis and cancer therapies, there has been a recent emphasis on researching programmed cell death (PCD). In the current study, we discovered the enriched and prognostic PCD in ccRCC utilizing gene set enrichment analysis (GSEA) and investigate the functional status of ccRCC patients with different PCD risks. Then, genes related to PCD that had prognostic value in ccRCC were identified for the conduction of non-negative matrix factorization to cluster ccRCC patients. Next, the tumor microenvironment, immunogenicity, and therapeutic response in different molecular clusters were analyzed. Among PCD, apoptosis and pyroptosis were enriched in ccRCC and correlated with prognosis. Patients with high PCD levels were related to poor prognosis and a rich but suppressive immune microenvironment. PCD-based molecular clusters were identified to differentiate the clinical status and prognosis of ccRCC. Moreover, the molecular cluster with high PCD levels may correlate with high immunogenicity and a favorable therapeutic response to ccRCC. Furthermore, a simplified PCD-based gene classifier was estab-lished to facilitate clinical application and used transcriptome sequencing data from clinical ccRCC samples to validate the applicability of the gene classifier. We thoroughly extended the understanding of PCD in ccRCC and constructed a PCD-based gene classifier for differentiation of the prognosis and therapeutic efficacy in ccRCC.

Automated summary

In this study, we investigated the role of programmed cell death (PCD) in clear cell renal cell carcinoma (ccRCC) and developed a PCD-based gene classifier for prognosis and therapeutic efficacy differentiation in ccRCC. Through gene set enrichment analysis (GSEA), we identified enriched and prognostic PCD in ccRCC and explored the functional status of ccRCC patients with different PCD risks. We also analyzed the tumor microenvironment, immunogenicity, and therapeutic response in different molecular clusters. Our findings suggest that PCD, specifically apoptosis and pyroptosis, is correlated with prognosis in ccRCC and that high PCD levels are associated with poor prognosis and a suppressive immune microenvironment.