gms | German Medical Science

The evidence for a causal association between tobacco smoking and colorectal cancer is accumulating. The susceptibility to carcinogens may, however, be influenced by the individual genetic make-up. N-acetyltransferases (NAT) are involved in the metabolism of heterocyclic and aromatic amines, both of which are present in tobacco smoke. Genetic polymorphisms in the NAT1 and NAT2 genes may therefore modify the association between smoking and colorectal cancer risk.

We conducted a population-based case-control study in southern Germany. A total of 514 incident colorectal cancer patients and 610 age and sex-matched controls with information on genotype and detailed history on active and passive smoking were included in the analysis. Genotyping of polymorphisms in the NAT1 and NAT2 genes was performed by capillary based real-time PCR followed by melting curve analysis. For the genotype-based assignment of NAT2 acetylator status, the point mutations C481T, G590A, A803G and G857A were analyzed. Individuals were classified as NAT2 fast acetylators if they possessed at least one wild-type NAT2*4 allele. To distinguish homozygous and heterozygous carriers of the NAT1*10 allele from non-carriers of the NAT1*10 allele, the polymorphisms T1088A, C1095A and G560A were investigated. Multivariate conditional logistic regression analysis was used to estimate the association between genotype, smoking and colorectal cancer risk.

Neither NAT1 nor NAT2 genotype was an independent risk factor for colorectal cancer. Risk estimates for active smoking did not differ appreciably by NAT1 genotype or NAT2 acetylator status. When both genotypes were combined, we observed an increased risk associated with more than 20 pack-years of smoking among NAT2 slow acetylators not carrying the NAT1*10 allele (OR 1.6, 95% CI 1.0-2.7), i.e. those with presumably low acetylation capacity, but not among NAT2 fast acetylators who were carriers of the NAT1*10 allele (OR 1.2, 95% CI 0.5-3.1) or the other genotype combinations (OR 0.9; 95% CI 0.5-1.5). Among never active smokers, exposure to passive smoking was associated with an increased risk of colorectal cancer among NAT2 fast acetylators but not among NAT2 slow acetylators (ORs for exposure to former passive smoking were 2.0, 95% CI 1.0-4.1 and 0.6, 0.3-1.0, respectively). The test for multiplicative interaction, however, did not reach statistical significance (p=0.07).

Our findings suggest that NAT1 and NAT2 genotypes individually are not strong modifiers of smoking-associated colorectal cancer risk. However, low acetylation capacity due to combined NAT1 and NAT2 genotypes may increase colorectal cancer risk associated with heavy active smoking. In addition, NAT2 acetylator status may alter susceptibility to passive smoking, suggesting that some heterocyclic amines, which are contained at higher levels in sidestream smoke than in mainstream smoke, may contribute significantly to carcinogenesis associated with exposure to passive smoking.