The Impact of Germline Genetic Variations in Hydroxysteroid (17-Beta) Dehydrogenases on Prostate Cancer Outcomes After Prostatectomy

Abstract

BackgroundThe relationship between polymorphisms in the hydroxysteroid (17-beta) dehydrogenase (HSD17B) family of genes, which are involved in steroid hormone biotransformation, and the risk of prostate cancer (PCa) progression remains unexplored. ObjectiveDetermine whether inherited variations in HSD17B genes are associated with PCa progression. Design, setting, and participantsWe studied two independent Caucasian cohorts composed of 526 men with organ-confined PCa and 213 men with advanced disease who had a median follow-up of 7.4 yr and 7.8 yr after surgery, respectively. MeasurementsPatients with localised PCa were genotyped for 88 haplotype-tagging single nucleotide polymorphisms in HSD17B type 1 (HSD17B1), type 2 (HSD17B2), type 3 (HSD17B3), type 4 (HSD17B4), type 5 (HSD17B5), and type 12 (HSD17B12), and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings were then investigated in advanced disease. Results and limitationsAfter adjusting for known risk factors, 12 SNPs distributed across HSD17B2, HSD17B3, and HSD17B12 were significantly associated with risk of biochemical recurrence (BCR) in localised PCa (for variants in HSD17B2: hazard ratio [HR]: 1.92–2.93; p=0.025–0.004). In addition, four variants of HSD17B2 (rs1364287, rs2955162, rs1119933, rs9934209) were significantly associated with progression-free survival (HR: 2.96–4.69; p=0.004–0.00005) and overall survival in advanced disease (HR: 3.98–8.14; p=0.003–0.00002). Four variants of HSD17B3 and HSD17B12 were associated with a reduced risk of BCR (HR: 0.51–0.65; p=0.020–0.036) but not with progression in advanced disease. These results were generated mainly in Caucasians and should be studied in other ethnic groups. ConclusionsThis study suggests a prominent role for common genetic variants in the HSD17B2 pathway in PCa progression.