Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer

被引：1333

作者：

Beltran, Himisha ^{[1
,2
,3
]}

Prandi, Davide ^{[4
]}

Mosquera, Juan Miguel ^{[1
,5
]}

Benelli, Matteo ^{[4
]}

Puca, Loredana ^{[1
]}

Cyrta, Joanna ^{[1
]}

Marotz, Clarisse ^{[1
]}

Giannopoulou, Eugenia ^{[6
]}

Chakravarthi, Balabhadrapatruni V. S. K. ^{[7
]}

Varambally, Sooryanarayana ^{[7
]}

Tomlins, Scott A. ^{[8
]}

Nanus, David M. ^{[2
,3
]}

Tagawa, Scott T. ^{[2
,3
]}

Van Allen, Eliezer M. ^{[9
,10
]}

Elemento, Olivier ^{[1
,6
]}

Sboner, Andrea ^{[1
,5
,11
]}

Garraway, Levi A. ^{[9
,10
,12
,13
]}

Rubin, Mark A. ^{[1
,3
,5
]}

Demichelis, Francesca ^{[1
,4
,11
]}

机构：

[1] Weill Cornell Med, New York Presbyterian Hosp, Caryl & Israel Englander Inst Precis Med, New York, NY USA

[2] Weill Cornell Med, Div Hematol & Med Oncol, Dept Med, New York, NY USA

[3] Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY USA

[4] Univ Trento, Ctr Integrat Biol, Trento, Italy

[5] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY USA

[6] Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA

[7] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

[8] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[9] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Broad Inst MIT & Harvard Univ, Cambridge, MA USA

[11] Weill Cornell Med, Inst Computat Biomed, New York, NY USA

[12] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02115 USA

[13] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA

来源：

NATURE MEDICINE | 2016年 / 22卷 / 03期

基金：

美国国家卫生研究院; 欧洲研究理事会;

关键词：

SMALL-CELL CARCINOMA; INCREASED SURVIVAL; EZH2; ADENOCARCINOMA; ENZALUTAMIDE; PROGRESSION; ABIRATERONE; REPRESSION; SIGNATURE; ESTROGEN;

D O I：

10.1038/nm.4045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：298 / 305

页数：8

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