Format

Send to

Choose Destination
Nat Genet. 2016 Dec;48(12):1490-1499. doi: 10.1038/ng.3692. Epub 2016 Oct 17.

Clonal evolution of chemotherapy-resistant urothelial carcinoma.

Author information

1
Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.
2
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.
3
Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA.
4
Centre for Integrative Biology, University of Trento, Trento, Italy.
5
Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
8
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.
9
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.

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.

PMID:
27749842
PMCID:
PMC5549141
DOI:
10.1038/ng.3692
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center