Multi-omics analysis uncovers clinical, immunological, and pharmacogenomic implications of cuproptosis in clear cell renal cell carcinoma

Objective The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective. Methods This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation. Results Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients' survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group. Conclusion Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.