Novel Ferroptosis-Related Multigene Prognostic Models for Patients with Bladder Cancer

Objective: Bladder cancer contributes to a serious disease burden in clinical settings. The characteristics and prognosis of patients with muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) are distinctly different. The study aims to figure out the respective role of ferroptosis in MIBC and NMIBC and to construct ferroptosis-related gene signatures that could predict patients' prognoses. Methods: A total of 608 MIBC and 414 NMIBC RNA-seq transcriptome data with intact clinical and follow-up information were downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and Gene expression omnibus (GEO) database. Ferroptosis-related multigene prognostic models were constructed and externally validated, respectively, in MIBC and NMIBC. Further functional enrichment analyses were also performed to explicate the underlying mechanisms and the differences between the two bladder cancer subtypes. Results: In MIBC, a 7-gene signature for prognostic prediction was constructed. Patients were then divided into high-risk and low-risk groups according to the risk scores calculated by the 7-gene prognostic model. Patients in the high-risk group presented an impaired OS when compared with patients in the low-risk group both in the training cohort and validation cohort. Further functional analyses revealed distinctly different immune statuses between the two risk-stratification groups, speculating that exhausted immune cell function was a cause of the worst OS in the high-risk group. In NMIBC, 6 ferroptosis-related genes were identified that were significantly correlated with recurrence-free survival (RFS). Similarly, a 6-gene prognostic model was constructed and verified as an independent prognostic predictor for RFS. Functional analyses revealed significant differences in the expressions of nuclear division genes between the high-risk group and low-risk group. Conclusion: Two novel ferroptosis-related multigene prognostic models for, respectively, predicting OS in MIBC and RFS in NMIBC were identified in this study, which indicated ferroptosis played vital roles in the oncogenesis and development of MIBC and NMIBC.