Alternative splicing patterns reveal prognostic indicator in muscle-invasive bladder cancer

Background Bladder cancer is one of the most lethal malignancy in urological system, and 20-25% of bladder cancer patients are muscle invasive with unfavorable prognosis. However, the role of alternative splicing (AS) in muscle-invasive bladder cancer (MIBC) remains to be elucidated. Methods Percent spliced in (PSI) data obtained from the Cancer Genome Atlas (TCGA) SpliceSeq database (n = 394) were utilized to evaluate the AS events in MIBC. Prognosis-associated AS events were screened out by univariate Cox regression. LASSO Cox regression was used to identify reliable prognostic patterns in a training set and further validated in a test set. Splicing regulatory networks were constructed by correlations between PSI of AS events and RNA expression of splicing factors. Results As a result, a total of 2589 prognosis-related AS events in MIBC were identified. Pathways of spliceosomal complex (FDR = 0.017), DNA-directed RNA polymerase II, core complex (FDR = 0.032), and base excision repair (FDR = 0.038) were observed to be significantly enriched. Additionally, we noticed that most of the prognosis-related AS events were favorable factors. According to the LASSO and multivariate Cox regression analyses, 15-AS-based signature was established with the area under curve (AUC) of 0.709, 0.823, and 0.857 at 1-, 3-, and 5- years, respectively. The MIBC patients were further divided into high- and low-risk groups based on median risk sores. Interestingly, we observed that the prevalence of FGFR3 with mutations and focal amplification was significantly higher in low-risk group. Functional and immune infiltration analysis suggested potential signaling pathways and distinct immune states between these two groups. Moreover, splicing correlation network displayed a regulatory mode of prognostic splicing factors (SF) in MIBC patients. Conclusions This study not only provided novel insights into deciphering the possible mechanism of tumorgenesis and pathogenesis but also help refine risk stratification systems and potential treatment of decision-making for MIBC.

Automated summary

This study identified 2589 prognosis-related alternative splicing (AS) events in muscle-invasive bladder cancer (MIBC). Enriched pathways, such as spliceosomal complex, DNA-directed RNA polymerase II core complex, and base excision repair, were observed. A signature based on 15 AS events was established and showed good predictive ability for prognosis in MIBC patients. FGFR3 mutations and focal amplification were associated with low-risk MIBC patients. Functional and immune infiltration analysis revealed potential signaling pathways and distinct immune states between high- and low-risk groups. Furthermore, a splicing correlation network demonstrated the regulatory mode of prognostic splicing factors in MIBC patients.