Phase II Drug-Metabolizing Polymorphisms and Smoking Predict Recurrence of Non-Muscle-Invasive Bladder Cancer: A Gene-Smoking Interaction.

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.