👤 Chantal Guillemette

Prostate cancer is a heterogeneous genetic disease, and molecular methods for predicting prognosis in patients with aggressive form of the disease are urgently needed to better personalize treatment approaches. The objective was to identify host genetic variations in candidate steroidogenic genes affecting hormone levels and prostate cancer progression. The study examined two independent cohorts composed of 526 Caucasian men with organ-confined prostate cancer and 601 Taiwanese men on androgen-deprivation therapy. Caucasians were genotyped for 109 haplotype-tagging single-nucleotide polymorphisms (SNP) in CYP17A1, ESR1, CYP19A1, and HSD3B1, and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings, including previously identified SRD5A1, SRD5A2, HSD17B2, HSD17B3, and HSD17B12 polymorphisms, were then explored in Taiwanese men (n = 32 SNPs). The influence of positive markers on the circulating hormonal levels was then appraised in Caucasians using specific and sensitive mass spectrometry-based methods. After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229 and rs7201637), and ESR1 (rs1062577) were associated with progressive disease in both cohorts. Indeed, the presence of these variations was significantly associated with progression in Caucasians (HR, 2.29-4.10; P = 0.0014-2 × 10(-7)) and survival in Taiwanese patients [HR = 3.74; 95% confidence interval (CI): 1.71-8.19, P = 0.009]. Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P = 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P = 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P ≤ 0.05). This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2, and ESR1 as attractive prognostic molecular markers of prostate cancer progression. Show less

The 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. Determine whether inherited variations in HSD17B genes are associated with PCa progression. We 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. Patients 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. After 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. This study suggests a prominent role for common genetic variants in the HSD17B2 pathway in PCa progression. Show less