Revealing prognostic and tumor microenvironment characteristics of cuproptosis in bladder cancer by genomic analysis

Objectives: Bladder cancer (BLCA) is the most common malignant tumor in the urinary system, while the prognosis of muscle-invasive bladder cancer (MIBC) is poor. Cuproptosis might be a promising therapeutic approach to trigger tumor cell death. This study aimed to figure out the role of cuproptosis in BLCA and constructed a new cuproptosis scoring system to guide clinical diagnosis and individualize treatments. Methods: Consensus clustering was used to classify 490 patients with BLCA from TCGA and GEO cohorts. Survival outcomes and functional enrichment analyses were performed between the different subtypes. The cuproptosis scoring system was constructed by LASSO-Cox analysis. ESTIMATE, CIBERSORT, and ssGSEA were used to investigate the tumor microenvironment (TME). Drug sensitivity was evaluated with pRRophetic. An immunotherapy cohort was used to investigate the treatment response. The cuproptosis scoring system was verified in our own cohort with quantitative real-time PCR. Results: An overview of 12 cuproptosis genes (CuGs) in the TCGA database was depicted. Based on the mRNA expression profiles of CuGs, patients were classified into two cuproptosis molecular patterns. Based on the differential genes between the two cuproptosis patterns, the patients were classified into two cuproptosis gene clusters. There were distinct survival outcomes, signaling pathways, and TME between the two subtypes. A 7-gene cuproptosis scoring system was constructed. Patients with high cuproptosis scores showed worse OS and more immunosuppressing TME than those with low cuproptosis scores. The two cuproptosis score groups had distinct mutation profiles. Patients with high cuproptosis scores tended to be sensitive to chemotherapy drugs, but insensitive to immune checkpoint inhibitors (ICIs) treatment. Conclusion: This study depicted the landscape of cuproptosis in BLCA. We constructed a cuproptosis scoring system to predict the prognosis of BLCA patients. There were significant differences in survival outcomes, TME, mutation profiles, and drug sensitivities in high and low cuproptosis score patients. The cuproptosis scoring system could help oncologists comprehensively understand the tumor characteristic of BLCA and make individualized treatment strategies.