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Clonal evolution of chemotherapy-resistant urothelial carcinoma

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 1 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 1 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.

J Clin Oncol 35. © 2017 by American Society of Clinical Oncology

Authors: Bishoy M Faltas1–3,10, Davide Prandi4,10, Scott T Tagawa1–3, Ana M Molina1,2, David M Nanus1–3,
Cora Sternberg5, Jonathan Rosenberg6, Juan Miguel Mosquera1,7, Brian Robinson1,7, Olivier Elemento1,8,9, Andrea Sboner1,7,9, Himisha Beltran1–3,11, Francesca Demichelis1,4,9,11 & Mark A Rubin1,3,7,11

Author Affiliations: 1Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital–Weill Cornell Medicine, New York, New York, USA. 2Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA. 3Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA. 4Centre for Integrative Biology, University of Trento, Trento, Italy. 5Department of Medical Oncology, San Camillo–Forlanini Hospital, Rome, Italy. 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. 7Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA. 8Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA. 9Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA. 10These authors contributed equally to this work. 11These authors jointly directed this work. Correspondence should be addressed to M.A.R. () or F.D. ().
Received 21 May; accepted 9 September; published online 17 October 2016; doi:10.1038/ng.3692

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