Background: Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compared 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.

Authors: Brian R. Winters, MD,1 Navonil De Sarkar, PhD,2,3 Sonali Arora, MD,3 Hamid Bolouri, PhD,3 Sujata Jana, PhD,3 Funda Vakar-Lopez, MD,4 Heather H. Cheng, MD,2 Michael T. Schweizer, MD,2 Evan Y. Yu, MD,2  Petros Grivas, MD,2 John K. Lee, MD, PhD,2,3 Lori Kollath,1 Sarah K. Holt,1 Lisa McFerrin, PhD,5 Gavin Ha,5 Peter S. Nelson, MD,2,3 Robert B. Montgomery, MD,2 Jonathan L. Wright, MD, MS, FACS,1,5 Hung-Ming Lam, PhD1,6 and Andrew C. Hsieh, MD2,3
1. Department of Urology and
2. Department of Medicine, Division of Oncology, University of Washington School of Medicine, Seattle, Washington, USA.
3. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
4. Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
5. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
6. Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.

Winters, B., De Sarkar, N., Arora, S., Bolouri, H., Jana, S., & Vakar-Lopez, F. et al. (2019). Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy. JCI Insight. 2019;4(13):e128728.