Clonal evolution of chemotherapy-resistant urothelial carcinoma Academic Article uri icon


MeSH Major

  • APOBEC-1 Deaminase
  • Carcinoma, Transitional Cell
  • Clonal Evolution
  • Drug Resistance, Neoplasm
  • Mutagenesis
  • Mutation
  • Neural Cell Adhesion Molecule L1
  • Urinary Bladder Neoplasms


  • Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.

publication date

  • December 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC5549141

Digital Object Identifier (DOI)

  • 10.1038/ng.3692

PubMed ID

  • 27749842

Additional Document Info

start page

  • 1490

end page

  • 1499


  • 48


  • 12