Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer

Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associated with increased risk of colorectal cancer. Aromatic amines (aryl- and heterocyclic) are a class of carcinogens that are important in these exposures. These compounds can be N- or O-acetylated by the NAT1 or NAT2 enzymes, resulting in activation or in some cases detoxification. Recent studies have shown that both NAT2 and NAT1 genes exhibit variation in human populations and that rapid acetylation by the NAT2 enzyme may be a risk factor for colorectal cancer. In this study we have analyzed for genetic polymorphism in both NAT1 and NAT2 in a group of 202 colorectal cancer patients and 112 control subjects from Staffordshire, England. We find significantly increased risk (odds ratio, 1.9; 95% confidence interval, 1.2-3.2; P = 0.009) associated with the NAT1*10 allele of NAT1, an allele that contains a variant polyadenylation signal. Individuals with higher stage tumors (Duke's C) were more likely to inherit this variant allele (odds ratio, 2.5; 95% confidence interval, 1.3-4.7; P = 0.005). In contrast, rapid acetylation genotypes of NAT2 were not a significant risk factor in this English population. However, we found that the risk associated with the NAT1 variant allele (NAT1*10) was most apparent among NAT2 rapid acetylators (odds ratio, 2.8; 95% confidence interval, 1.4-5.7; P = 0.003), suggesting a possible gene-gene interaction between NAT1 and NAT2 (test for interaction; P = 0.12). This is the first study to test for cancer risk associated with the NAT1 gene, and these positive findings suggest that NAT1 alleles may be important genetic determinents of colorectal cancer risk.