THE ROLE OF N-ACETYLATION POLYMORPHISMS IN SMOKING-ASSOCIATED BLADDER-CANCER - EVIDENCE OF A GENE-GENE-EXPOSURE 3-WAY INTERACTION

Arylamines are known bladder carcinogens and are an important constitu ent of tobacco smoke. The handling of arylamines in the body is comple x and includes metabolism by NAT1 and NAT2, enzymes that play a role i n both activation and detoxification of arylamines and their congeners . Both NAT1 and NAT2 are polymorphic, with alleles that have been show n to correlate with higher or lower enzyme activity. To explore the co mbined role of these genes and exposure on bladder cancer risk, we exa mined the NAT1 and NAT2 genotype in a case-control study of bladder ca ncer in which detailed exposure histories were available on all 230 ca ses and 203 frequency-matched controls. Using PCR-RFLP genotyping, we determined NAT2 genotype for the five most common alleles, NAT24, NAT 25, NAT2*6, NAT2*7, NAT2*14 (frequently referred to as WT, M1, M2, M3 , and M4, respectively). Similarly, the NAT1 genotype was determined f or the four most common alleles NAT13, NAT1*4 and NAT1*11, and the pu tative high-activity allele, NAT110, No association between NAT2 geno type and bladder cancer risk was found whether genotype was considered alone or in combination with smoking, in either stratified or logisti c regression analysis that adjusted for age, sex, and race. Stratified and logistic regression analysis both demonstrated an increased risk for individuals carrying the NAT110 allele among smokers. There was e vidence of a gene-dosage effect, such that those who were homozygous f or the NAT110 allele had the highest risks. There was also evidence o f a statistically significant gene-environment interaction, such that bladder cancer risk depends on both NAT1 genotype and smoking exposure . Interestingly, although NAT2 genotype did not influence risk either alone or in combination with smoking exposure, there was evidence of a statistically significant gene-gene-environment three-way interaction . Bladder cancer risk from smoking exposure is particularly high in th ose who inherit NAT2 slow alleles in combination with one or two copie s of the NAT110 allele. A biological mechanism for this finding is su ggested.