Beltran, HimishaPrandi, DavideMosquera, Juan MiguelBenelli, MatteoPuca, LoredanaCyrta, JoannaMarotz, ClarisseGiannopoulou, EugeniaChakravarthi, Balabhadrapatruni V.S.K.Varambally, SooryanarayanaTomlins, Scott A.Nanus, David M.Tagawa, Scott T.Van Allen, EliezerElemento, OlivierSboner, AndreaGarraway, LeviRubin, Mark A.Demichelis, Francesca2016-10-112016Beltran, H., D. Prandi, J. M. Mosquera, M. Benelli, L. Puca, J. Cyrta, C. Marotz, et al. 2016. “Divergent clonal evolution of castration resistant neuroendocrine prostate cancer.” Nature medicine 22 (3): 298-305. doi:10.1038/nm.4045. http://dx.doi.org/10.1038/nm.4045.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002436An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, wherein tumor cells demonstrate low to absent AR expression and often neuroendocrine features. The etiology and molecular basis for these “alternative” treatment-resistant cell states remain incompletely understood. Here, by analyzing whole exome sequencing data of metastatic biopsies from patients, we observed significant genomic overlap between castration resistant adenocarcinoma (CRPC-Adeno) and neuroendocrine histologies (CRPC-NE); analysis of serial progression samples points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno that also designated cases 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.en-USJournal Article2016-10-1110.1038/nm.4045