GENETIC RISK AND CARCINOGEN EXPOSURE - A COMMON INHERITED DEFECT OF THE CARCINOGEN-METABOLISM GENE GLUTATHIONE-S-TRANSFERASE M1 (GSTM1) THAT INCREASES SUSCEPTIBILITY TO BLADDER-CANCER

Background: Numerous studies have associated bladder cancer with expos ure to carcinogens present in tobacco smoke and other environmental or occupational exposures. Approximately 50% of all humans inherit two d eleted copies of the GSTM1 gene which encodes for the carcinogen-detox ification enzyme glutathione S-transferase M1. Recent findings suggest that the GSTM1 gene may modulate the internal dose of environmental c arcinogens and thereby affect the risk of developing bladder cancer. P urpose: We investigated whether the absence of the GSTM1 gene affects bladder cancer risk and whether there are racial differences in GSTM1 genotype frequency. Methods: Using a polymerase chain reaction (PCR)-b ased method, we examined the frequency of the homozygous deleted genot ype (GSTM1 0/0) in 229 patients with transitional cell carcinoma of th e bladder and 211 control subjects who were enrolled from the Urology Clinics at Duke University Medical Center and the University of North Carolina Hospitals. Control subjects were urology clinic patients who primarily presented with benign prostatic hypertrophy or impotence, wh o had no history of any cancer other than nonmelanoma skin cancer, and who were frequency matched to case patients on race, sex, and age (10 -year age intervals). In order to explore racial differences in GSTM1 gene frequency, genotype was also determined in a community-based samp le of 466 paid, healthy, unrelated volunteers from Durham and Chapel H ill, N.C. The presence or absence of the GSTM1 gene locus was determin ed by using a differential PCR, a semiquantitative technique in which multiple genes are coamplified. Results: Overall, the GSTM1 0/0 genoty pe conferred a 70% increased risk of bladder cancer (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.2-2.5; P = .004). Absence of th e GSTM1 gene encoding the glutathione S-transferase M1 enzyme signific antly increased risk to persons with exposure to the carcinogens in to bacco smoke (OR = 1.8; 95% CI = 1.2-3.0; P = .01) but poses little inc reased risk to persons without such exposure. Persons with smoking exp osure of more than 50 pack-years who had the GSTM1 0/0 genotype had a sixfold greater risk relative to persons in the lowest risk group (i.e ., nonsmokers who were GSTM1 +/+ or +/0). In the pooled clinic control and community sample groups (677 individuals), the GSTM1 0/0 genotype occurred less frequently among Blacks (35%) than among Whites (49%, P <.001). Conclusions: These findings support a protective role for the GSTM1 gene in bladder cancer. From these findings, it is estimated tha t 25% of all bladder cancer may be attributable to the at-risk GSTM1 0 /0 genotype.