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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 13668 (11 29 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27897170 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AR protein, human
• RNA, Messenger
• Receptors, Androgen

Topics

• Alleles
• Cell Line, Tumor
• Chromosomes, Human, Pair 11 (genetics)
• Clone Cells
• Exons (genetics)
• Gene Dosage
• Gene Expression Regulation, Neoplastic
• Gene Rearrangement (genetics)
• Genome, Human
• Humans
• Male
• Neoplasm Metastasis
• Prostatic Neoplasms, Castration-Resistant (genetics)
• RNA, Messenger (genetics, metabolism)
• Receptors, Androgen (metabolism)