Abstract PR06: Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy

Abstract

Abstract Introduction: Exceedingly little is known about the genomic difference between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We evaluated and 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 37 tumor samples from 7 patients with metastatic UC collected between 2015-2017 via rapid autopsy, with matched primary and metastatic tumor samples. Inter- and intrapatient analyses of mutational burden, mutational signatures, predicted deleterious mutations (somatic single nucleotide variations [sSNV] and insertions-deletions), and somatic copy alterations (sCNV) were conducted. Results: We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). Most patients were men, nonsmokers, and received cisplatin-based therapy. We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature that has been described in localized bladder cancer was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intraindividual 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 our patient population with the majority shared across all metastases within a patient. Conclusions: In these patients, 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, which may in part explain differences in aggressive clinical behavior. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients. This abstract is also being presented as Poster B09. Citation Format: 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. Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR06.