Comprehensive Genomic Characterization Between Urothelial Carcinoma Subtypes/Divergent Differentiation (S/ DD ) and Pure Urothelial Carcinoma Using a Large‐Scale Japanese Genomic Panel Dataset

OBJECTIVES: Urothelial carcinoma (UC) is a common malignancy; however, UC subtypes/divergent differentiation (S/DD) accounts for only 10%-20% of overall cases. S/DD's aggressive biological behavior significantly affects its prognosis and therapeutic decision-making; thus, elucidating its genomic landscape within UC is important. This retrospective observational study aimed to evaluate and compare the molecular characteristics of S/DD and pure urothelial carcinoma (PUC). METHODS: Comprehensive cancer genomic profiling data were obtained from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and the MSK2022 dataset. The association between S/DD and clinicopathological features was evaluated in an independent Hiroshima University cohort. RESULTS: Across both C-CAT and MSK2022 datasets, TP53 and RB1 mutations were more prevalent in S/DD, whereas KDM6A, ARID1A, and FGFR3 mutations were more common in PUC. High-frequency copy number alterations included MYC and RB1 in S/DD, and CDKN2A, CDKN2B, CCND1, FGF19, FGF4, and FGF3 in PUC. In the Hiroshima University cohort, S/DD was associated with adverse clinicopathological features and a poor prognosis. Immunohistochemistry demonstrated a positive correlation of S/DD with PD-L1, EGFR, and p53 expression in upper tract UC tissues, and an inverse correlation with FGFR3, GATA3, Nectin4, and TROP2 expression. CONCLUSIONS: Using a large-scale Japanese genomic panel dataset, we characterized the molecular alterations associated with S/DD. S/DD frequently exhibits low Nectin-4 expression and basal-like molecular features, which may have implications for treatment selection and inform future therapeutic strategies.