Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC. Experimental Design: We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression ofARandtruncatedARvariants (AR-V). Results: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs andwere resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
Bibliographical noteFunding Information:
This study was supported by the Movember Foundation/Prostate Cancer Foundation Challenge Award (S.M. Dehm), NIH R01CA174777 (S.M. Dehm), and U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-13-2-0093 (to S.R. Plymate and S.M. Dehm). The University of Washington Prostate Cancer Donor Rapid Autopsy Program was supported by the Department of Defense Prostate Cancer Biorepository Network (PCBN; W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1 CA163227), and the Institute for Prostate Cancer Research (IPCR). We thank the patients and their families. We acknowledge Celestia Higano, Evan Yu, Elahe Mostaghel, Heather Cheng, Pete Nelson, Bruce Montgomery, Mike Schweizer, Daniel Lin, Eva Corey, Funda Vakar-Lopez, Lawrence True, and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program.
© 2020 American Association for Cancer Research.