Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.

Nat Med
Authors
Keywords
Abstract

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.

Year of Publication
2016
Journal
Nat Med
Volume
22
Issue
3
Pages
298-305
Date Published
2016 Mar
ISSN
1546-170X
URL
DOI
10.1038/nm.4045
PubMed ID
26855148
PubMed Central ID
PMC4777652
Links
Grant list
P50 CA090381 / CA / NCI NIH HHS / United States
U01CA162148 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
R01 CA183857 / CA / NCI NIH HHS / United States
R01 CA157845 / CA / NCI NIH HHS / United States
1K08CA188615 / CA / NCI NIH HHS / United States
5U01 CA111275-09 / CA / NCI NIH HHS / United States
R01 CA116337 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States
R01CA157845 / CA / NCI NIH HHS / United States