Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Transfers
  • Current issue
  • Past issues
  • By specialty
  • Contact
  • Recently published
  • Technical Advances
  • Clinical Medicine
  • Editorials
  • Top read articles
Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy
Brian R. Winters, … , Hung-Ming Lam, Andrew C. Hsieh
Brian R. Winters, … , Hung-Ming Lam, Andrew C. Hsieh
Published July 11, 2019; First published May 30, 2019
Citation Information: JCI Insight. 2019;4(13):e128728. https://doi.org/10.1172/jci.insight.128728.
View: Text | PDF
Categories: Clinical Medicine Oncology

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

  • Text
  • PDF
Abstract

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.

Authors

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

×

Figure 2

Metastatic UTUC tumors exhibit more deleterious private mutations compared with metastatic LTUC tumors.

Options: View larger image (or click on image) Download as PowerPoint
Metastatic UTUC tumors exhibit more deleterious private mutations compar...
(A) Heatmap representing the absolute number of predicted deleterious genes mutated that are shared between all pairs of tumors, revealing limited interpatient homogeneity across both UTUC (n = 16) and LTUC (n = 21). Here, we constructed a per-gene binary indicator vector for every tumor and calculated the number of affected genes that are shared between all pairs of tumors, which are plotted in the matrix. The numbers of shared mutations are indicated by the color scale. LN, lymph node. (B) Intrapatient predicted deleterious mutations across UTUC (blue) and LTUC (yellow) tumors represented as a percentage of all shared (colored), semishared (present in >1 sample), and private (mutated only in single samples) mutations. Left, both primary and metastatic specimens; right, metastases only (P values calculated using the χ2 test). (C) Representative bladder cancer TCGA mutations identified in our patient cohort as well as genes identified by gene set enrichment analysis (tumor-suppressive p53 pathway FDR = 6.09 × 10–4, and oncogenic MAPK signaling pathway FDR = 8.98 × 10–6).
Follow JCI Insight:
Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts