Abstract B065: Genomic analysis of localized prostate cancer identifies AZIN1 as driver of metastatic progression

Abstract

Abstract High-risk PCa (HRPCa) remains very heterogeneous with an unacceptable variation in patient outcome after radical prostatectomy, with cancer-specific mortality rates ranging from 4.6% to 20.3% at 10 years’ follow-up. Clearly, we need a better understanding of the tumor biology to enhance the subclassification, enable the identification of lethal PCa, and eventually allow a more precise decision-making regarding treatment. We created a matched case-control study of two clinically identical HRPCa patient groups, both treated with radical prostatectomy but where one developed metastatic recurrence (n=19) and the other did not (n=25), despite very-long-term follow-up. The integrated analysis of copy number aberrations and transcriptome analysis highlighted a focal amplification of 8q22.3 in the metastatic group, associated with a higher expression of antizyme inhibitor 1 (AZIN1) in our cohort. This association of high AZIN1 levels with the metastatic HRPCa phenotype suggests a role for AZIN1 as possible predictor and/or target for metastatic HRPCa. AZIN1 is one of the regulators of the polyamine synthesis, which play a central role in many cellular processes. Our in vitro analyses confirmed that modulation of AZIN1 expression determines both growth and migratory potential of prostate cancer cells. Future experiments are planned to confirm these data in the in vivo setting. RNA sequencing after knockdown of AZIN1 in PCa cells revealed several transcriptional programs that are activated/deactivated upon AZIN1 knockdown. This showed among others a significant upregulation of genes involved in extracellular matrix composition, including genes encoding for subunits of the collagen IV, which is an integral part of the basement membrane. Ongoing experiments focus on identifying the mechanism by which AZIN1 regulates collagen IV expression. Citation Format: Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Elien Smeets, Stefan Prekovic, Christine Helsen, Hendrik van Poppel, Wouter Everaerts, Christine Buerki, Elai Davicioni, Steven Joniau, Frank Claessens. Genomic analysis of localized prostate cancer identifies AZIN1 as driver of metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B065.