Prognostic Significance of the Cytoplasmic Expression of UDP-glucuronosyltransferase 2B17 in Localized Prostate Cancer: Insights from the Canadian Prostate Cancer Biomarker Network and PROCURE Multi-institutional Cohorts.

Abstract

Background and objective: Prostate cancer (PCa) is hormone dependent, with UDP-glucuronosyltransferase 2B17 (UGT2B17) playing a central role in androgen inactivation. This study aimed to evaluate whether UGT2B17 expression in prostatectomy specimens can serve as a prognostic marker for lethal PCa.

Methods: A prespecified hypothesis posited that UGT2B17 expression (>25%) in primary tumors is associated with an aggressive disease phenotype, leading to metastasis, castration resistance (castration-resistant PCa [CRPC]), and mortality in men initially diagnosed with localized disease. Two high-density prostate tumor tissue microarray datasets were analyzed: the first from the Canadian Prostate Cancer Biomarker Network biobank (n = 1454) and the second from the PROCURE cohort (n = 1562). Kaplan-Meier and Cox proportional hazard ratio analyses were used to evaluate metastasis-free survival, CRPC, and PCa-specific mortality. Steroid levels were measured in plasma samples by mass spectrometry, and a linear regression model was used to evaluate variations in hormone levels based on tumoral UGT2B17 expression.

Key findings and limitations: UGT2B17 was associated with prognostic factors and linked to elevated levels of androsterone glucuronide (60%), the major circulating androgen-inactive metabolite, which is inactivated by UGT2B17. Kaplan-Meier and multivariable Cox analyses revealed that higher tumoral UGT2B17 is associated with an increased risk of progression to metastatic/CRPC stages and with PCa-specific mortality.

Conclusions and clinical implications: UGT2B17 expression influences hormone levels and identifies a subset of patients at an increased risk of progression to an incurable disease stage. Findings support the notion that enhanced UGT2B17, through increased androgen inactivation, creates a low-androgen tumor environment that drives tumor progression to a more aggressive phenotype.