Integrative genomic analysis examines molecular and clinical disparities between bladder urothelial carcinoma and upper tract urothelial carcinoma.

e16553 Background: The clinical outcome of urothelial carcinoma presents significant variability, reflecting its intricate molecular composition, epidemiologic attributes, and primary site of origin. Despite histological similarities, upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) represent two distinct disease entities with disparate treatment responses and mutational patterns. Methods: To assess the impact of molecular heterogeneity on treatment outcomes, we conducted a comprehensive genomic analysis of 231 Korean BLCA and UTUC patients from the K-MASTER cohort. Results: Our investigation unveiled dynamic molecular properties and mutational patterns in key molecules, including TP53, FGFR3, CREBBP, and SPEN. BLCA patients demonstrated enrichment of APOBEC mutational signature activities, whereas UTUC patients were characterized by activation of the cell cycle pathway. Transcriptome analysis uncovered unique biological signatures, highlighting increased cell migration and WNT signaling in BLCA, while FGFR3 and stem-cell-like pathways predominated in UTUC. Moreover, our study identified increased treatment resistance to both platinum-based chemotherapy and immunotherapy in UTUC patients. Notably, tumor mutational burden (TMB) and microsatellite instability score independently demonstrated robust predictive capabilities for immunotherapy response in BLCA and UTUC, respectively. Lastly, a machine learning-based multivariable model identified FGFR3 mutation as a molecular determinant associated with favorable clinical outcomes, contrasting with mutations in FGFR2 linked to increased resistance to chemotherapy. Conclusions: Collectively, our findings provide important insights into the significance of molecular and clinical disparities in urothelial carcinoma, facilitating disease-specific treatment interventions.