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 and Scott M. Dehm ()
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Christine Henzler: Minnesota Supercomputing Institute, University of Minnesota
Yingming Li: Masonic Cancer Center, University of Minnesota
Rendong Yang: Minnesota Supercomputing Institute, University of Minnesota
Terri McBride: Masonic Cancer Center, University of Minnesota
Yeung Ho: Masonic Cancer Center, University of Minnesota
Cynthia Sprenger: University of Washington
Gang Liu: University of Washington
Ilsa Coleman: Fred Hutchinson Cancer Research Center
Bryce Lakely: University of Washington
Rui Li: University of Texas Southwestern Medical Center
Shihong Ma: University of Texas Southwestern Medical Center
Sean R. Landman: University of Minnesota
Vipin Kumar: University of Minnesota
Tae Hyun Hwang: Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center
Ganesh V. Raj: University of Texas Southwestern Medical Center
Celestia S. Higano: Fred Hutchinson Cancer Research Center
Colm Morrissey: University of Washington
Peter S. Nelson: Fred Hutchinson Cancer Research Center
Stephen R. Plymate: University of Washington
Scott M. Dehm: Masonic Cancer Center, University of Minnesota

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13668

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