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

Author

Listed:
  • 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
    Medical Scientist Training Program, 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
    University of Washington
    University of Washington)

  • Colm Morrissey

    (University of Washington)

  • Peter S. Nelson

    (Fred Hutchinson Cancer Research Center)

  • Stephen R. Plymate

    (University of Washington
    University of Washington
    Geriatric Research Education and Clinical Centers, VA Puget Sound Health Care System)

  • Scott M. Dehm

    (Masonic Cancer Center, University of Minnesota
    University of Minnesota)

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.

Suggested Citation

  • 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 H, 2016. "Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13668
    DOI: 10.1038/ncomms13668
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    Cited by:

    1. Todd P. Knutson & Bin Luo & Anna Kobilka & Jacqueline Lyman & Siyuan Guo & Sarah A. Munro & Yingming Li & Rakesh Heer & Luke Gaughan & Michael J. Morris & Himisha Beltran & Charles J. Ryan & Emmanuel , 2024. "AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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