Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma

Background: Metastatic urothelial carcinoma (mUC) is a lethal cancer for which few therapeutic options exist.  Methods: To define the molecular landscape of mUC and identify targets for therapy, we performed whole-genome DNA sequencing on fresh-frozen metastatic tumor biopsies of 116 mUC patients, and mRNA sequencing on 90 matched biopsies.  Results: Hierarchical clustering based on mutational signatures revealed two major genomic subtypes. The most prevalent subtype (67%) consisted of tumors with high APOBEC mutagenesis. Transcriptomic analysis revealed five mRNA-based subtypes: two luminal subtypes (40%), a stroma-rich (24%), basal/squamous (23%), and non-specified subtype (12%). The transcriptomic subtypes were different regarding driver gene alterations, gene amplifications, pathway activity, and immune cell infiltration. By integrating the genomic and transcriptomic data, potential therapeutic options per transcriptomic subtype and individual patient were proposed. Conclusions: This study serves as a reference for subtype-oriented and patient-specific research on the etiology of mUC, and for novel drug development.