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

Abstract

Purpose: 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.Experimental Design: 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 ¼ 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 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 ¼ 0.0014-2 Â 10 À7 ) and survival in Taiwanese patients [HR ¼ 3.74; 95% confidence interval (CI): 1.71-8.19,Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P ¼ 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P ¼ 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P 0.05).

Steroidogenic Germline Polymorphism Predictors of Prostate Cancer Progression in the Estradiol Pathway

“…We excluded patients who had received neoadjuvant hormone treatment and those with missing genotype information for the studied SNPs. Steroids were measured by validated gas chromatography-mass spectrometry or liquid chromatography-tandem mass spectrometry (4). Deuterated steroids were added into each sample, and quality controls were included in each run.…”

“…Coefficients of variation for the intra-and interassays were 10.0%, and accuracy values (given in parentheses) were T (100.5%), DHT (103.5%), ADT (96.5%), ADT-G (99.5%), 3a-diol-3G (89.2%), 3a-diol-17G (100.2%), DHEA (96.13%), DHEA-S (99.9%), E 1 -S (100.45%), E 1 (106.9%), E 2 (103.15%), 4-dione (95.5%), and 5-diol (95.33%; ref. 4).…”

“…Another useful and much simpler approach to predict prostate cancer outcomes relies on identifying key inherited genetic variations involved in disease progression (4,5). In fact, potential molecular determinants of clinical outcomes have been identified as components encoded by immune system genes (6, 7), sex steroid-related genes (4,8), and, with conflicting results, prostate cancer risk alleles (9)(10)(11)(12). The importance of studying host steroidogenic pathways comes from observations that prostate cells possess the enzymatic machinery for intracrine conversion of precursors into more potent Authors' Affiliations:…”

“…Moreover, the consequence of sustained and active steroidogenesis in cancer cells is highlighted by the observation that castration-resistant prostate cancer can still be driven by sex steroid hormones despite a low circulating testosterone (T) level (14). Several germline polymorphisms in sex steroid metabolic pathways have been shown to be associated with localized and advanced prostate cancer outcomes related to a meaningful influence of inherited genetic variations in the androgenic pathway on progression (4,8). Therefore, in addition to tumor markers, circulating tumor cells, and whole-blood gene-expression profiles (2,3,16), host polymorphisms might assist in predicting tumor behavior and serve as a simple and reliable assay easily analyzed from germline DNA of any human.…”

The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy

“…Germline variations in genes involved in the biosynthesis and metabolism of androgens and estrogens have been associated with progression of PCa , Levesque et al 2013, 2014a. The relevance of studying steroidogenic pathways in the context of progression of PCa arises from observations that PCa tumor cells can use multiple biotransforming pathways to de novo synthesize more potent hormones (Montgomery et al 2008, Mitsiades et al 2012.…”