|Title||Clonal evolution of chemotherapy-resistant urothelial carcinoma.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Faltas 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|
|Date Published||2016 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 Journal||Nat. Genet.|