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

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124 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

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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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, Article 13668. https://doi.org/10.1038/ncomms13668

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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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.",

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AU - Nelson, Peter S.

AU - Plymate, Stephen R.

AU - Dehm, Scott M.

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

Abstract

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