Comparative genomic landscape of primary and metastatic bladder urothelial carcinoma in a large-scale cohort.

Metastatic bladder urothelial carcinoma has poor survival, and large comparative genomic studies using uniform targeted sequencing of paired primary and metastatic lesions remain limited. We compared gene- and pathway-level alterations between primary and metastatic tumors METHODS: We analyzed 2,880 bladder urothelial carcinoma samples (2,305 primary; 575 metastatic) from 2,343 patients profiled with MSK-IMPACT. Somatic mutations and copy number alterations were integrated per gene and compared between primary and metastatic samples in the full cohort and in a paired subset using standard statistical tests. Primary and metastatic samples showed broadly similar driver landscapes. In the full cohort, KDM6A, FGFR3, STAG2, and ERCC2 were more frequently altered in primary tumors, whereas no individual genes were enriched in metastases; these differences were not significant in paired analyses. At the pathway level, TP53 pathway alterations were relatively more frequent in metastases, while DNA damage response alterations were enriched in primary tumors; other pathways showed comparable alteration rates. Apoptosis-focused analyses identified no significant gene-level differences, but suggested a trend toward higher alteration rates in the TP53 pathway and apoptosis regulators in metastases. Primary and metastatic lesions of bladder urothelial carcinoma show broadly similar gene- and pathway-level alteration profiles on targeted DNA sequencing. TP53 pathway and apoptosis-related alterations are modestly more frequent in metastases, consistent with impaired stress responses and apoptosis evasion.