title: Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
abstract: An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
authors: 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: Himisha
authors: H
authors: Beltran
authors: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors: Davide
authors: D
authors: Prandi
authors: 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: Juan Miguel
authors: JM
authors: Mosquera
authors: Centre for Integrative Biology, University of Trento, Trento, Italy.
authors: Matteo
authors: M
authors: Benelli
authors: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.
authors: Loredana
authors: L
authors: Puca
authors: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.
authors: Joanna
authors: J
authors: Cyrta
authors: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA.
authors: Clarisse
authors: C
authors: Marotz
authors: Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.
authors: Eugenia
authors: E
authors: Giannopoulou
authors: Department of Pathology, University of Alabama, Birmingham, Alabama, USA.
authors: Balabhadrapatruni V S K
authors: BV
authors: Chakravarthi
authors: Department of Pathology, University of Alabama, Birmingham, Alabama, USA.
authors: Sooryanarayana
authors: S
authors: Varambally
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Scott A
authors: SA
authors: Tomlins
authors: 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: David M
authors: DM
authors: Nanus
authors: 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: Scott T
authors: ST
authors: Tagawa
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
authors: Eliezer M
authors: EM
authors: Van Allen
authors: 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.
authors: Olivier
authors: O
authors: Elemento
authors: 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: Andrea
authors: A
authors: Sboner
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Levi A
authors: LA
authors: Garraway
authors: 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: Mark A
authors: MA
authors: Rubin
authors: 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: Francesca
authors: http://orcid.org/0000-0002-8266-8631
authors: F
authors: Demichelis
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary; D060965:Clonal Evolution / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000556:secondary; D011446:Prospective Studies; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D011944:Receptors, Androgen