title: Clonal evolution of chemotherapy-resistant urothelial carcinoma.
abstract: 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.
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.
authors.forename: Bishoy M
authors.initials: BM
authors.lastname: Faltas
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prandi
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Tagawa
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Molina
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.affiliation: Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Cora
authors.initials: C
authors.lastname: Sternberg
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.|Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.|Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Centre for Integrative Biology, University of Trento, Trento, Italy.|Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Francesca
authors.identifier: 0000-0002-8266-8631
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.|Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.|Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Mark A
authors.identifier: 0000-0002-8321-9950
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D000071479:APOBEC-1 Deaminase / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics*; D011446:Prospective Studies; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D039842:Neural Cell Adhesion Molecule L1; D000071479:APOBEC-1 Deaminase