title: Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer.
abstract: BACKGROUND
  The prognostic relevance of inherited variations in hormone-related genes in the context of prostate cancer (PCa) progression has not been well studied. Of these, UDP-glucuronosyltransferase (UGT) gene products lead to inactivation of steroids.
  
  
  OBJECTIVE
  Our objective was to determine whether polymorphisms in five UGT genes, involved in steroid metabolism, are associated with the risk of biochemical recurrence after radical prostatectomy (RP) and to examine their relationship with hormonal exposure.
  
  
  METHODS
  The study included 526 Caucasian and 320 Asian men who underwent RP for clinically localized PCa. The relationship between genotypes and biochemical recurrence were assessed with multivariate Cox proportional hazard models. Plasma steroids were measured using specific and sensitive mass spectrometry-based methods.
  
  
  RESULTS
  The presence of at least two deleted copies of UGT2B17 and UGT2B28 genes resulted in a hazard ratio of 2.26 (95% confidence interval = 1.41-3.61; P = 0.0007) for Caucasians and 2.16 (95% confidence interval = 1.24-3.73; P = 0.006) for Asians. A positive association was observed only between UGT2B17 deletion and the Gleason score in Asians, whereas no other interaction was shown with prostate-specific antigen, Gleason score, and TNM (tumor node metastasis) staging. Patients carrying UGT2B17 deletions and those with three deleted UGT2B copies had significantly lower androgen glucuronides, in support of an altered androgen metabolism.
  
  
  CONCLUSIONS
  This study is the first to recognize the prognostic significance of common deletions in steroid inactivation pathways in localized PCa after RP. Alteration of circulating steroid levels associated with UGT2B gene deletions further support the notion that such inherited genomic deletions have the potential to modify hormonal exposure and risk of recurrence.
authors: Pharmacogenomics Laboratory, Centre Hospitalier de l'Université Laval CHUQ Research Center, and Faculty of Pharmacy, and L'Hôtel-Dieu de Quebec, CHUQ Research Center and Faculty of Medicine, Laval University, Québec, Canada.
authors: Geneviève
authors: G
authors: Nadeau
authors: Judith
authors: J
authors: Bellemare
authors: Étienne
authors: É
authors: Audet-Walsh
authors: Christine
authors: C
authors: Flageole
authors: Shu-Pin
authors: SP
authors: Huang
authors: Bo-Ying
authors: BY
authors: Bao
authors: Pierre
authors: P
authors: Douville
authors: Patrick
authors: P
authors: Caron
authors: Yves
authors: Y
authors: Fradet
authors: Louis
authors: L
authors: Lacombe
authors: Chantal
authors: C
authors: Guillemette
authors: Eric
authors: E
authors: Lévesque
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000097:blood; D018450:Disease Progression; D017353:Gene Deletion; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000601:surgery
chemical_list: D000728:Androgens; D014453:Glucuronosyltransferase; D017430:Prostate-Specific Antigen