Analysis of AR Gene Rearrangements in Prostate Cancer

Molecularly-targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signaling 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 tumors. 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 tumors within and between patients. Despite this heterogeneity, one common outcome in tumors 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 signaling in CRPC.]]>
Metastatic CRPC samples were obtained from patients who died of CRPC in 2000-2013 and who signed written informed consent for a rapid autopsy performed within 6 h of death, under the aegis of the Prostate Cancer Donor Program at the University of Washington. Localized CRPC samples were obtained under written informed consent by transurethral resection of the prostate (TURP) procedures performed for obstructive uropathy at University of Texas Southwestern Medical Center. Hormone naive prostate cancer tissues from patients with biopsy-confirmed prostate cancer (Gleason Score 6-9) were obtained under written informed consent at the time of radical prostatectomy from the University of Texas Southwestern Medical Center tissue core under UTSW IRB STU 112013-056.]]>