Divergent clonal evolution of castration resistant neuroendocrine prostate cancer

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Beltran, Himisha
Prandi, Davide
Mosquera, Juan Miguel
Benelli, Matteo
Puca, Loredana
Cyrta, Joanna
Marotz, Clarisse
Giannopoulou, Eugenia
Chakravarthi, Balabhadrapatruni V.S.K.
Varambally, Sooryanarayana
Tomlins, Scott A.
Nanus, David M.
Tagawa, Scott T.
Elemento, Olivier
Sboner, Andrea
Rubin, Mark A.
Demichelis, Francesca
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nm.4045Metadata
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Beltran, 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.Abstract
An 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777652/pdf/Terms of Use
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