title: SRD5A polymorphisms and biochemical failure after radical prostatectomy.
abstract: BACKGROUND
  The relationship between inherited germ-line variations in the 5α-reductase pathways of androgen biosynthesis and the risk of biochemical recurrence (BCR) after radical prostatectomy (RP) remains an unexplored area.
  
  
  OBJECTIVE
  To determine the link between germ-line variations in the steroid-5α-reductase, α-polypeptide 1 (SRD5A1) and steroid-5α-reductase, α-polypeptide 2 (SRD5A2) genes and BCR.
  
  
  METHODS
  We studied retrospectively two independent cohorts composed of 526 white (25% BCR) and 320 Asian men (36% BCR) with pathologically organ-confined prostate cancer who had a median follow-up of 88.8 and 30.8 mo after surgery, respectively.
  
  
  METHODS
  Patients were genotyped for 19 haplotype-tagging single nucleotide polymorphisms (htSNPs) in SRD5A1 and SRD5A2 genes, and their prognostic significance on prostate-specific antigen recurrence was assessed using Kaplan-Meier analysis and the Cox regression model.
  
  
  CONCLUSIONS
  After adjusting for all clinicopathologic risk factors, four SNPs (rs2208532, rs12470143, rs523349, and rs4952197) were associated with BCR in both whites and Asians. The strongest effect was conferred by the SRD5A2 V89L nonsynonymous SNP (rs523349C) with a hazard ratio (HR) of 2.87 (95% confidence interval [CI], 2.07-4.00; p = 4 × 10⁻¹⁰; 48% BCR). In addition, in whites, the combination of two SNPs, rs518673T in SRD5A1 and rs12470143A in SRD5A2, was associated with a reduced BCR rate for carriers of three or four alleles (HR: 0.37; 95% CI, 0.19-0.71; p=0.003;16% BCR) compared with noncarriers (38% BCR), whereas the SRD5A2 rs12470143A was significant in Asians (HR: 0.46; 95% CI, 0.28-0.73; p=0.001). Limitations of our study include few events of androgen-deprivation resistance or cancer-specific death.
  
  
  CONCLUSIONS
  Our study is the first to show positive associations of several SRD5A1 and SRD5A2 variations as independent predictors of BCR after RP.
authors.affiliation: Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec (CHUQ) Research Centre and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Audet-Walsh
authors.forename: Judith
authors.initials: J
authors.lastname: Bellemare
authors.forename: Geneviève
authors.initials: G
authors.lastname: Nadeau
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.forename: Vincent
authors.initials: V
authors.lastname: Fradet
authors.forename: Shu-Pin
authors.initials: SP
authors.lastname: Huang
authors.forename: Bo-Ying
authors.initials: BY
authors.lastname: Bao
authors.forename: Pierre
authors.initials: P
authors.lastname: Douville
authors.forename: Hugo
authors.initials: H
authors.lastname: Girard
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
authors.forename: Eric
authors.initials: E
authors.lastname: Lévesque
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy / Q000009:adverse effects*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000208:ethnology / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D011792:Quebec / Q000453:epidemiology; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013624:Taiwan / Q000453:epidemiology; D017211:Treatment Failure; D044465:White People / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548467:SRD5A1 protein, human; C548468:SRD5A2 protein, human; D017430:Prostate-Specific Antigen