Divergent clonal evolution of castration resistant neuroendocrine prostate cancer
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Divergent clonal evolution of castration resistant neuroendocrine prostate cancer
| Title: | Divergent clonal evolution of castration resistant neuroendocrine prostate cancer |
| Author: |
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.; Van Allen, Eliezer M.; Elemento, Olivier; Sboner, Andrea; Garraway, Levi A.; Rubin, Mark A.; Demichelis, Francesca
Note: Order does not necessarily reflect citation order of authors. |
| Citation: | 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. |
| Full Text & Related Files: |
4777652.pdf (822.5Kb; PDF) 
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| 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. |
| Published Version: | doi:10.1038/nm.4045 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777652/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002436 |
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