title: The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy.
abstract: The prognostic significance of common deletions in uridine diphospho-glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at the UGT1 locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants of UGT1 are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across the UGT1 locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan-Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for four UGT1 intronic variants with hazard ratios (HRs) of 1.59-1.88 (P<0.002) for htSNPs in UGT1A10, UGT1A9, and UGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns of UGT1A10 and UGT1A9 (HR=0.56-058; P≤0.01). An unfavorable UGT1 haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CI=1.13-2.50; P=0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms of UGT1 are potential predictors of recurrence of PCa after prostatectomy.
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Laverdière
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Flageole
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Étienne
authors.initials: É
authors.lastname: Audet-Walsh
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Lévesque
authors.affiliation: Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada Pharmacogenomics LaboratoryCentre Hospitalier Universitaire de Québec (CHU de Québec) Research Center and Faculty of Pharmacy, Laval University, R4720, 2705 Boulevard Laurier, Québec, Québec, Canada G1V 4G2CHU de Québec Research Center and Faculty of MedicineLaval University, Québec, Québec, CanadaCanada Research Chair in PharmacogenomicsQuébec, Québec, Canada chantal.guillemette@crchudequebec.ulaval.ca.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056426:Genetic Loci; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics*; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000601:surgery*; D012307:Risk Factors
chemical_list: D014453:Glucuronosyltransferase
keywords: UGT; biochemical recurrence; germline polymorphisms; glucuronidation; prostate cancer