BACKGROUND Little is known about the genomic differences between metastatic lower tract 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) collected via rapid autopsy of 7 patients with metastatic urothelial carcinoma. Inter- and intrapatient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy number variations (sCNVs) 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 somatic single-nucleotide variant (sSNV) burden was higher in metastatic LTUC compared with UTUC. Moreover, the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (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 UTUC demonstrated a lower overall mutational burden but greater structural variability compared with 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.FUNDING NIH, Seattle Translation Tumor Research Program in Bladder Cancer, Howard J. Cohen Bladder Cancer Foundation, Johns Hopkins Greenberg Bladder Cancer Institute, Department of Defense Prostate Cancer Research Program, American Association for Cancer Research, Burroughs Wellcome Fund, David Matthews, and the Stinchcomb Memorial Funds.


Brian R. Winters, Navonil De Sarkar, Sonali Arora, Hamid Bolouri, Sujata Jana, Funda Vakar-Lopez, Heather H. Cheng, Michael T. Schweizer, Evan Y. Yu, Petros Grivas, John K. Lee, Lori Kollath, Sarah K. Holt, Lisa McFerrin, Gavin Ha, Peter S. Nelson, Robert B. Montgomery, Jonathan L. Wright, Hung-Ming Lam, Andrew C. Hsieh


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