title: Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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 = 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmacogenomics Laboratory and L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec (CHUQ) Research Center, Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Lévesque
authors.forename: Shu-Pin
authors.initials: SP
authors.lastname: Huang
authors.forename: Étienne
authors.initials: É
authors.lastname: Audet-Walsh
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.forename: Bo-Ying
authors.initials: BY
authors.lastname: Bao
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Laverdière
authors.forename: Mélanie
authors.initials: M
authors.lastname: Rouleau
authors.forename: Chao-Yuan
authors.initials: CY
authors.lastname: Huang
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Yu
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People / Q000235:genetics; D014408:Biomarkers, Tumor; D018450:Disease Progression; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D013256:Steroids / Q000097:blood / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012739:Gonadal Steroid Hormones; D013256:Steroids