title: Importance of 5α-reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer.
abstract: OBJECTIVE
  Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5α-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer.
  
  
  METHODS
  To gain potential insights into SRD5A biologic effects, we examined the relationship between SRD5A prognostic markers and endogenous sex-steroid levels measured by mass spectrometry in plasma samples and corresponding prostatic tissues of patients with prostate cancer.
  
  
  RESULTS
  We report that five of the seven SRD5A markers differentially affect sex-steroid profiles of dihydrotestosterone and its metabolites in both the circulation and prostatic tissues of patients with prostate cancer. Remarkably, a 32% increase in intraprostatic testosterone levels was observed in the presence of the high-risk SRD5A rs2208532 polymorphism. Moreover, SRD5A2 markers were associated predominantly with circulating levels of inactive glucuronides. Indeed, the rs12470143 SRD5A2 protective allele was associated with high circulating androstane-3α, 17β-diol-17-glucuronide (3α-diol-17G) levels as opposed to lower levels of both 3α-diol-17G and androsterone-glucuronide observed with the rs2208532 SRD5A2 risk allele. Moreover, SRD5A2 rs676033 and rs523349 (V89L) risk variants, in strong linkage disequilibrium, were associated with higher circulating levels of 3α-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5α-reduced steroids (dihydrotestosterone and its metabolite 3β-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids.
  
  
  CONCLUSIONS
  Our data support the association of 5α-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5α-reductase inhibitor efficacy.
authors.affiliation: Authors' Affiliations: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy; and Centre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Lévesque
authors.forename: Isabelle
authors.initials: I
authors.lastname: Laverdière
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.forename: Mélanie
authors.initials: M
authors.lastname: Rouleau
authors.forename: Véronique
authors.initials: V
authors.lastname: Turcotte
authors.forename: Bernard
authors.initials: B
authors.lastname: Têtu
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000728:Androgens; D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548467:SRD5A1 protein, human; C548468:SRD5A2 protein, human