A genomic analysis of metastases-prone localized prostate cancer identifies AZIN1 as driver of metastatic progression.

Introduction

Patients with high-risk prostate cancer (PCa) treated with radical prostatectomy are at an increased risk of metastatic progression and death from PCa. Currently the driver genes of localized high-risk tumors remain unexplored mainly due to unavailability of tissues of patients with very long-term follow-up.

Materials and Methods

Patients who developed distant metastases after radical prostatectomy for high-risk, non-metastatic prostate cancer in a tertiary referral centre were matched to patients who did not develop distant metastases, but had significant longer follow-up (n=70). Formalin-fixed paraffin-embedded tissue blocks from the index PCa lesion were used for DNA and RNA extraction which were used for copy number aberration (CNA) and gene expression analysis. For in vitro experiments, standard molecular biology methods were performed.

Results and conclusion

Somatic CNA analyses of the primary tumor revealed significantly more focal amplifications in the cohort with metastatic recurrence. In total, 2599 genes are located within these chromosomal regions. Integrative CNA and gene expression analysis revealed that altered expression of AZIN1, located within a focal 8q22.3 amplification was most significantly associated with metastatic recurrence, which was validated in four independent patient cohorts. In vitro analyses validated that modulating AZIN1 gene expression in the PC3 cell line mimicked the metastatic phenotype observed in patient data. Upon knockdown of AZIN1, RNA-sequencing revealed an upregulation of genes involved in extracellular matrix organisation, such as genes involved in collagen deposition and basal membrane organisation. Further investigations are focused on the mechanisms how AZIN1 regulates the extracellular matrix organisation in PCa. These findings will be essential in understanding tumor biology and potentially lead to the development of novel drugs.