Molecular markers in Key Steroidogenic Pathways, Circulating steroid levels and Prostate Cancer progression
Menée sur deux cohortes indépendantes comportant respectivement 526 hommes de type caucasien atteints d'un cancer localisé de la prostate et 601 hommes taïwanais recevant un traitement anti-androgénique, cette étude analyse l'association entre 109 polymorphismes à simple nucléotide de 4 gènes (CYP17A1, ESR1, CYP19A1 et HSD3B1), les niveaux plasmatiques d'hormones stéroïdiennes et la progression de la maladie
Purpose: Prostate cancer (PCa) 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 PCa progression. Experimental Design: The study examined two independent cohorts composed of 526 Caucasian men with organ-confined PCa and 601 Taiwanese men on androgen-deprivation therapy (ADT). Caucasians were genotyped for 109 haplotype-tagging SNPs in CYP17A1, ESR1, CYP19A1, 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, 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. Results: After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229, 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 values of 2.29-4.10; p=0.0014-2X10-7) and survival in Taiwanese patients (HR=3.74 95%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). Conclusion: This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2 and ESR1 as attractive prognostic molecular markers of PCa progression.
Clinical Cancer Research , résumé, 2012