期刊
NATURE MEDICINE
卷 22, 期 3, 页码 298-305出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.4045
关键词
-
资金
- Damon Runyon Cancer Research Foundation [CI-67-13]
- Ann and William Bresnan Foundation
- Department of Defense [PC121341]
- US National Institutes of Health (NIH) [R01 CA116337, R01CA157845, R01 CA183857, 1K08CA188615, U54 HG003067, U01CA162148, 5U01 CA111275-09]
- Starr Cancer Consortium
- American-Italian Cancer Foundation
- Nuovo Soldati Foundation
- A. Alfred Taubman Medical Institute
- Prostate Cancer Foundation Young Investigator Award
- Associazione Italians per la Ricerca sul Cancro (AIRC) [IG 13562]
- European Research Council
- Prostate Cancer Foundation
- Stand Up To Cancer-Prostate Cancer Foundation Prostate Dream Team translational cancer research grant
- Entertainment Industry Foundation [SU2C-AACR-DT0712]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据