Faculty Collaboration Database

Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy. JCI Insight 2019 May 30;5(13)

Date

05/31/2019

Pubmed ID

31145100

Pubmed Central ID

PMC6629128

DOI

10.1172/jci.insight.128728

Scopus ID

2-s2.0-85070658429 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

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.

Author List

Winters BR, De Sarkar N, Arora S, Bolouri H, Jana S, Vakar-Lopez F, Cheng HH, Schweizer MT, Yu EY, Grivas P, Lee JK, Kollath L, Holt SK, McFerrin L, Ha G, Nelson PS, Montgomery RB, Wright JL, Lam HM, Hsieh AC

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Autopsy
Carcinoma, Transitional Cell
Female
Genomics
Humans
Male
Middle Aged
Mutation
Sequence Analysis
Urologic Neoplasms