Distinct molecular signatures of upper tract urothelial carcinoma in Southwestern Taiwan: implications for targeted therapy and disease progression

The incidence of upper tract urothelial carcinoma (UTUC) continues to rise in Southwestern Taiwan, despite a reduction in known environmental carcinogens. This study aimed to characterize the mutational and molecular profiles of UTUC in this high-incidence region and evaluate potential therapeutic targets. We performed next-generation sequencing using the TruSight Oncology 500 panel on 19 formalin-fixed, paraffin-embedded UTUC samples. We analyzed single nucleotide variants (SNVs), insertions/deletions (INDELs), copy number variants (CNVs), microsatellite instability (MSI), and tumor mutational burden (TMB). MSI was stable in all cases, and 42.1% of samples exhibited high TMB (>20 mutations/Mb), often co-occurring with inactivation of TP53, BRCA1, or BRCA2. CNVs were significantly more frequent in advanced-stage UTUC (46.2%) than in early-stage disease (0%). FGFR3 mutations were enriched in early-stage tumors (83.3%), while TP53 mutations predominated in advanced-stage tumors (46.2%). Notably, actionable mutations in PIK3CA, ERBB2, BRCA1, and BRCA2 occurred at higher frequencies than in previously reported Japanese UTUC cohorts. Our findings reveal a distinct molecular signature of UTUC in Southwestern Taiwan, with early- and late-stage tumors showing divergent mutational landscapes. These insights emphasize the importance of molecular stratification in UTUC management and suggest that a broader repertoire of targeted therapies could benefit patients in this high-incidence region.