Clonal evolution of chemotherapy-resistant urothelial carcinoma.

TitleClonal evolution of chemotherapy-resistant urothelial carcinoma.
Publication TypeJournal Article
Year of Publication2016
AuthorsFaltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, rosenberg jonathan, Mosquera JMiguel, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA
JournalNat Genet
Date Published2016 Dec

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.

Alternate JournalNat. Genet.
PubMed ID27749842