Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer

• Published in: Nature medicine Vol. 22; no. 3; pp. 298 - 305
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2016; Nature Publishing Group
• Subjects: 45/23; 45/91; 631/208/2489/2487/2486; 692/699/67/589/466; Adenocarcinoma - genetics; Adenocarcinoma - secondary; Aged; Aged, 80 and over; Analysis; Androgens; Biomedicine; Bone Neoplasms - genetics; Bone Neoplasms - secondary; Cancer Research; Care and treatment; Clonal Evolution - genetics; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Hormone receptors; Humans; Infectious Diseases; letter; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Male; Metabolic Diseases; Middle Aged; Molecular Medicine; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - secondary; Neurosciences; Patient outcomes; Physiological aspects; Prospective Studies; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - genetics; Retrospective Studies; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4045

Genome-wide DNA methylation analysis of metastatic biopsies from patients with castration-resistant prostate cancer reveals marked epigenetic differences between samples with adenocarcinoma and neuroendocrine histologies. 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.