Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive molecular characterization is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen metastatic tumor biopsies from 116 mUC patients who were scheduled for palliative systemic treatment within the context of a clinical trial (NCT01855477 and NCT02925234). Hierarchical clustering for mutational signatures revealed two major genomic subtypes: GenS1 (67%), which was APOBEC-driven; and GenS2 (24%), which had a high fraction of de novo mutational signatures related to reactive oxygen species and is putatively clock-like. Significantly mutated genes (SMGs) did not differ between the genomic subtypes. Transcriptomic analysis revealed five mUC subtypes: luminal-a and luminal-b (40%), stroma-rich (24%), basal/squamous (23%), and a nonspecified subtype (12%). These subtypes differed regarding expression of key genes, SMGs, oncogenic pathway activity, and immune cell infiltration. We integrated the genomic and transcriptomic data to propose potential therapeutic options by transcriptomic subtype and for individual patients. This in-depth analysis of a large cohort of patients with mUC may serve as a reference for subtype-oriented and patient-specific research on the etiology of mUC and for novel drug development. PATIENT SUMMARY: We carried out an in-depth analysis of the molecular and genetic features of metastatic cancer involving the cells that line the urinary tract. We showed that this is a heterogeneous disease with different molecular subtypes and we identified possible targets for therapy for each subtype.
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