LAUSR

BACKGROUND Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease. METHODS We performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy alterations (sCNV) were analyzed. RESULTS We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intra-individual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across patients with the majority shared across all metastases within a patient. CONCLUSIONS Metastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients.