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.
Highlights
Bladder cancer is the 11th most common malignancy and the 14th leading cause of cancer worldwide with 382,700 new cases diagnosed in 2008 [1]
The first group consisted of 131 patients from a bank of 382 newly diagnosed patients with Non–muscle-invasive bladder cancer (NMIBC) recruited between September 1990 and April 1992 from 15 participating hospitals located in the province of Quebec, Canada [22]
Smoking is believed to be one of the main causes of bladder cancer, and similar to our findings, recent reports involved smoking for the risk of recurrence of NMIBC [9, 10]. In one of these reports, 46.8% of the ex- or current smokers were recurrence-free compared with 62.3% of nonsmokers after a mean follow-up of 2.5 years [9]
Summary
Bladder cancer is the 11th most common malignancy and the 14th leading cause of cancer worldwide with 382,700 new cases diagnosed in 2008 [1]. Cigarette smoking is the most important known risk factor for urinary bladder cancer, accounting for approximately 50% of all incident cases in men [4], possibly resulting in a reduced overall life expectancy in regular smokers [5]. In a case–control study, cigarette smoking was associated to the subtypes of bladder cancer, the odds associated with regular smokers being 2.2, 2.7, and 3.7 for low-grade NMIBC, high-grade NMIBC, and muscleinvasive tumors, respectively [8]. Smoking status significantly influences the recurrence-free survival [9, 10], and progression [10] of patients with NMIBC This is sustained by our observation, in a retrospective study of muscle-invasive bladder cancer, that smoking was an independent prognostic factor for recurrence and cancer-specific survival in patients treated with radical cystectomy [11]
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