Molecular Markers in Key Steroidogenic Pathways, Circulating Steroid Levels, and Prostate Cancer Progression

• Published in: Clinical cancer research Vol. 19; no. 3; pp. 699 - 709
• Main Authors: LEVESQUE, Eric, HUANG, Shu-Pin, CARON, Patrick, GUILLEMETTE, Chantal, AUDET-WALSH, Etienne, LACOMBE, Louis, BAO, Bo-Ying, FRADET, Yves, LAVERDIERE, Isabelle, ROULEAU, Mélanie, HUANG, Chao-Yuan, YU, Chia-Cheng
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2013
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic agents; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Biomarkers, Tumor; Disease Progression; European Continental Ancestry Group - genetics; Genotype; Gonadal Steroid Hormones - blood; Gonadal Steroid Hormones - metabolism; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Middle Aged; Neoplasm Grading; Neoplasm Staging; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - mortality; Prostatic Neoplasms - pathology; Signal Transduction; Steroids - blood; Steroids - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Steroid; Urinary system disease; Prostate disease; Genetic marker; Tumor progression; Malignant tumor; Molecular marker; Male genital diseases; Prostate cancer; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-2812

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.