N-acetyltransferase-2 genetic polymorphism, well-done meat intake, and breast cancer risk among postmenopausal women

Heterocyclic amines found in well-done meat require host-mediated metabolic activation before initiating DNA mutations and tumors in target organs. Po lymorphic N-acetyltransferase-2 (NAT2) catalyzes the activation of heterocy clic amines via O-acetylation, suggesting that NAT2 genotypes with high O-a cetyltransferase activity (rapid/intermediate acetylator phenotype) increas e the risk of breast cancer in women who consume well-done meat. To test th is hypothesis, DNA samples and information on diet and other breast cancer risk factors were obtained from a nested case-control study of postmenopaus al women. Twenty-seven NAT2 genotypes were determined and assigned to rapid , intermediate, or slow acetylator groups based on published characterizati ons of recombinant NAT2 allozymes. NAT2 genotype alone was not associated w ith breast cancer risk. A significant dose-response relationship was observ ed between breast cancer risk and consumption of well-done meat among women with the rapid/intermediate NAT2 genotype (trend test, P = 0.003) that was not evident among women with the slow acetylator genotype (trend test, P = 0.22). These results suggest an interaction between NAT2 genotype and meat doneness, although a test for multiplicative interaction was not statistic ally significant (P = 0.06), Among women with the rapid/intermediate NAT2 g enotype, consumption of well-done meat was associated with a nearly 8-fold (odds ratio, 7.6; 95% confidence interval, 1.1-50.4) elevated breast cancer risk compared with those consuming rare or medium-done meats. These result s are consistent with a role for O-acetylation in the activation of heteroc yclic amine carcinogens and support the hypothesis that the NAT2 acetylatio n polymorphism is a breast cancer risk factor among postmenopausal women wi th high levels of heterocyclic amine exposure.