Inherited Genetic Variations at the UGT1A Locus are Associated With Prostate Cancer Recurrence after Radical Prostatectomy

Background. Inherited variations in hormone-metabolizing genes such as UDP-glucuronosyltransferases (UGTs) have been studied for a possible association with prostate cancer (PCa) risk but their prognostic value in the context of recurrence after radical prostatectomy (RP) remains unexplored. Hypothesis and objective. Inherited genetic variations in UGTs, by modifying function/expression of the glucuronidation pathway, might significantly affect inactivation of sex-steroid hormones in a wide range of tissues including in residual prostate cancer cells following the surgical procedure, and alter subsequent risk of cancer recurrence. Our objective was to investigate UGT1A genetic variations as candidate prognostic markers and their relationships with circulating steroids. Study design. The study included 526 Caucasian men who underwent RP for clinically localized and locally advanced PCa with a median follow-up of 7.4 years. We genotyped 17 variants across the UGT1A locus previously reported to mark common variants in regulatory domains, exons and intron-exon boundaries. [1] Biochemical recurrence (BCR) risks were estimated using adjusted Cox proportional hazards regression and Kaplan-Meier analysis. We additionally investigated whether variants are predictive of plasma hormone levels using linear regression. Plasmas (n=500) collected the morning of the surgical procedure were available for endogenous steroid measures. Specific and sensitive mass spectrometry–based methods were used to quantify unconjugated (n=7) and conjugated (n=8) steroids. Analysis of covariance (ANCOVA) was used to compare means of log10-transformed hormonal variables between groups, adjusted for age. Results. Overall, 130 patients (24.7%) experienced PSA recurrence. As expected, preoperative PSA values and pathological biopsy Gleason scores were associated with BCR. After adjusting for these clinico-pathologic risk factors, a significant increased risk of BCR was revealed for 3 UGT1A tag SNPs. Hazard ratio (HR) values were of 1.59 (p=0.016) 1.77 (p=0.005) and 1.84 (p=0.003) for tag SNPs located in UGT1A8/UGT1A9. Furthermore, a reduced BCR risk was also observed in relation to an intronic UGT1A9 tag SNP (HR=0.56; p=0.003). No significant association was observed in the analysis of the functional UGT1A1*28 variant (rs34815109; c.–54/–53insTA) and other tag SNPs located in UGT1A3, UGT1A4, UGT1A6 or in the common 3’UTR region. Alterations in circulating steroids associated with some of these UGT1A genetic variants further support the notion that germline variations have the potential to modify hormonal exposure and risk of recurrence. Conclusion. This study provides the first evidence of UGT1A germline variations as potential biomarkers for prostate cancer recurrence. Predicting biochemical recurrence after radical prostatectomy in patients with clinically localized prostate cancer may thus be improved by taking into consideration patients’ genetic information related to the UGT genes. This work was supported by Prostate Cancer Canada. [1] Menard, V et al. Analysis of inherited genetic variations at the UGT1 locus in the French Canadian population. Hum Mutat. 2009. 30 (4): p. 677-87