Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.

TitleDivergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsBeltran H, Prandi D, Mosquera JMiguel, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BVSK, Varambally S, Tomlins SA, Nanus DM, Tagawa ST, Van Allen EM, Elemento O, Sboner A, Garraway LA, Rubin MA, Demichelis F
JournalNat Med
Date Published2016 Mar

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.

Alternate JournalNat. Med.
PubMed ID26855148
PubMed Central IDPMC4777652
Grant ListR01 CA116337 / CA / NCI NIH HHS / United States