Open AccessTruncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer
Author(s) -
Christine Henzler,
Yingming Li,
Rendong Yang,
Terri D. McBride,
Yeung Ho,
Cynthia T. Sprenger,
Gang Liu,
Ilsa M. Coleman,
Bryce Lakely,
Rui Li,
Shihong Ma,
Sean R. Landman,
Vijayendra Kumar,
Tae Hyun Hwang,
Ganesh V. Raj,
Celestia S. Higano,
Colm Morrissey,
Peter S. Nelson,
Stephen R. Plymate,
Scott M. Dehm
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms13668
Subject(s) - enzalutamide , abiraterone , androgen receptor , prostate cancer , context (archaeology) , cancer research , biology , transcriptional activity , chromoplexy , cancer , computational biology , genetics , gene expression , gene , pca3 , paleontology
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.