title: Phase II Drug-Metabolizing Polymorphisms and Smoking Predict Recurrence of Non-Muscle-Invasive Bladder Cancer: A Gene-Smoking Interaction.
abstract: Cigarette smoking is the most important known risk factor for urinary bladder cancer. Selected arylamines in cigarette smoke are recognized human bladder carcinogens and undergo biotransformation through several detoxification pathways, such as the glutathione S-transferases (GST), and uridine-diphospho-glucuronosyltransferases (UGT) pathways. GSTM1 deletion status and UGT1A1*28 rs8175347 genotypes were assessed in 189 non-muscle-invasive bladder cancers (NMIBC) patients with pTa (77.2%) and pT1 (22.8%) tumors and a mean follow-up of 5.6 years, to investigate whether two common functional polymorphisms in GSTM1 and UGT1A1 genes and smoking history are associated with recurrence-free survival of patients with NMIBC. Most patients were current (48.7%) or previous (35.4%) cigarette smokers and 15.9% never smoked. Tumor recurrence occurred in 65.1% of patients, at a median time of 12.9 months. Upon multivariate analysis, previous and current smokers approximately tripled their risk of recurrences [HR = 2.76; 95% confidence interval (CI), 1.03-7.40 and HR = 2.93; 95% CI, 1.08-7.94, respectively]. When adjusted for age, smoking status, stage, grade, gender, and presence of carcinoma in situ, carriers of GSTM1 (+/- and -/-) and UGT1A1*28/*28 alleles were significantly at risk of NMIBC recurrence (HR = 10.05; 95% CI, 1.35-75.1 and HR = 1.91; 95% CI, 1.01-3.62, respectively). Compared with nonsmokers with UGT1A1*1/*1 and *1/*28 genotypes, previous and current smokers homozygous for the UGT1A1*28 allele demonstrated a risk of recurrence of 4.95 (95% CI, 1.02-24.0) and 5.32 (95% CI, 2.07-13.7), respectively. This study establishes a connection between GSTM1, UGT1A1, and tobacco exposure as prognostic markers of NMIBC recurrence in bladder cancer patients. These findings warrant validation in larger cohorts.
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Department of Surgery (Urology), Faculty of Medecine, Laval University, Quebec, Canada. louis.lacombe@crchudequebec.ulaval.ca.
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Department of Surgery (Urology), Faculty of Medecine, Laval University, Quebec, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Fradet
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Faculty of Pharmacy, Laval University, Québec, Canada. Department of Medecine (Hemato-oncology), Faculty of Medecine, Laval University, Quebec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Lévesque
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Department of Surgery (Urology), Faculty of Medecine, Laval University, Quebec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pouliot
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Department of Surgery (Urology), Faculty of Medecine, Laval University, Quebec, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Larue
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Department of Surgery (Urology), Faculty of Medecine, Laval University, Quebec, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Bergeron
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Hovington
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Caron
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada.
authors.forename: Molière
authors.initials: M
authors.lastname: Nguile-Makao
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Harvey
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Department of Surgery (Urology), Faculty of Medecine, Laval University, Quebec, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.affiliation: Centre Hospitalier Universitaire (CHU) de Québec Research Center, Laval University, Québec, Canada. Pharmacogenomics Laboratory, Canada Research Chair in Pharmacogenomics, Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guillemette
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000099148:UGT1A1 Enzyme
chemical_list: D014408:Biomarkers, Tumor; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D000099148:UGT1A1 Enzyme