Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer

Christine Henzler; Yingming Li; Rendong Yang; Terri McBride; Yeung Ho; Cynthia Sprenger; Gang Liu; Ilsa Coleman; Bryce Lakely; Rui Li; Shihong Ma; Sean R. Landman; Vipin Kumar; Tae Hyun Hwang; Ganesh V. Raj; Celestia S. Higano; Colm Morrissey; Peter S. Nelson; Stephen R. Plymate; Scott M. Dehm

doi:10.1038/ncomms13668

Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer

Christine Henzler, Yingming Li, Rendong Yang, Terri McBride, Yeung Ho, Cynthia Sprenger, Gang Liu, Ilsa Coleman, Bryce Lakely, Rui Li, Shihong Ma, Sean R. Landman, Vipin Kumar, Tae Hyun Hwang, Ganesh V. Raj, Celestia S. Higano, Colm Morrissey, Peter S. Nelson, Stephen R. Plymate, Scott M. Dehm^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

110 Scopus citations

Abstract

Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.

Original language	English (US)
Article number	13668
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13668
State	Published - Nov 29 2016

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms13668

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Henzler, C., Li, Y., Yang, R., McBride, T., Ho, Y., Sprenger, C., Liu, G., Coleman, I., Lakely, B., Li, R., Ma, S., Landman, S. R., Kumar, V., Hwang, T. H., Raj, G. V., Higano, C. S., Morrissey, C., Nelson, P. S., Plymate, S. R., & Dehm, S. M. (2016). Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nature communications, 7, [13668]. https://doi.org/10.1038/ncomms13668

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title = "Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer",

abstract = "Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.",

author = "Christine Henzler and Yingming Li and Rendong Yang and Terri McBride and Yeung Ho and Cynthia Sprenger and Gang Liu and Ilsa Coleman and Bryce Lakely and Rui Li and Shihong Ma and Landman, {Sean R.} and Vipin Kumar and Hwang, {Tae Hyun} and Raj, {Ganesh V.} and Higano, {Celestia S.} and Colm Morrissey and Nelson, {Peter S.} and Plymate, {Stephen R.} and Dehm, {Scott M.}",

note = "Funding Information: We thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program. We acknowledge Drs Robert Vessella, Bruce Montgomery, Evan Yu, Elahe Mostaghel, Heather Cheng, Paul Lange, Martine Roudier and Lawrence True, and the tissue acquisition teams for their contributions to the University of Washington Prostate Cancer Donor Program. In addition, we thank Dr Eva Corey for access to LuCaP xenograft tissue and Belinda Nghiem for her technical expertise. This research was supported by funding from NIH grants R01CA174777 (to S.M.D.), U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-15-1-0430 (to S.R.P. and S.M.D.), the Pacific Northwest Prostate Cancer SPORE (P50CA97186 to P.S.N.), PO1 NIH grants (PO1CA085859 and PO1CA163227) and the Richard M. Lucas Foundation. T.M. was supported by NIH Medical Scientist Training Program grant T32GM008244. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

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Henzler, C, Li, Y, Yang, R, McBride, T, Ho, Y, Sprenger, C, Liu, G, Coleman, I, Lakely, B, Li, R, Ma, S, Landman, SR, Kumar, V, Hwang, TH, Raj, GV, Higano, CS, Morrissey, C, Nelson, PS, Plymate, SR & Dehm, SM 2016, 'Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer', Nature communications, vol. 7, 13668. https://doi.org/10.1038/ncomms13668

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T1 - Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer

AU - Henzler, Christine

AU - Li, Yingming

AU - Yang, Rendong

AU - McBride, Terri

AU - Ho, Yeung

AU - Sprenger, Cynthia

AU - Liu, Gang

AU - Coleman, Ilsa

AU - Lakely, Bryce

AU - Li, Rui

AU - Ma, Shihong

AU - Landman, Sean R.

AU - Kumar, Vipin

AU - Hwang, Tae Hyun

AU - Raj, Ganesh V.

AU - Higano, Celestia S.

AU - Morrissey, Colm

AU - Nelson, Peter S.

AU - Plymate, Stephen R.

AU - Dehm, Scott M.

N1 - Funding Information: We thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program. We acknowledge Drs Robert Vessella, Bruce Montgomery, Evan Yu, Elahe Mostaghel, Heather Cheng, Paul Lange, Martine Roudier and Lawrence True, and the tissue acquisition teams for their contributions to the University of Washington Prostate Cancer Donor Program. In addition, we thank Dr Eva Corey for access to LuCaP xenograft tissue and Belinda Nghiem for her technical expertise. This research was supported by funding from NIH grants R01CA174777 (to S.M.D.), U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-15-1-0430 (to S.R.P. and S.M.D.), the Pacific Northwest Prostate Cancer SPORE (P50CA97186 to P.S.N.), PO1 NIH grants (PO1CA085859 and PO1CA163227) and the Richard M. Lucas Foundation. T.M. was supported by NIH Medical Scientist Training Program grant T32GM008244. Publisher Copyright: © 2016 The Author(s).

PY - 2016/11/29

Y1 - 2016/11/29

N2 - Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.

AB - Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.

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JO - Nature Communications

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Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer

Abstract

ASJC Scopus subject areas

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