8p22

AAC1,MNAT,NAT-1,NATI

Lung cancer

Two independent studies have observed a significant association of the NAT1 polymorphism with lung cancer risk (Bouchardy et al., 1998; Wikman et al., 2001). However these studies should be interpreted cautiously because these do not agree on the NAT1 risk genotype. Another study identified an increased risk among carriers of NAT1 plus NAT2 slow genotypes (Gemignani et al., 2007). In a meta-analysis carried out with smokers that suffered from non small-cell lung cancer a relevant association of the NAT1 rapid acetylation genotype was identified (Zienolddiny et al., 2008). Although negative associations have been reported (Perera et al., 2006 ), NAT1 is emerging as the NAT gene most likely related to lung cancer (McKay et al, 2008).

Head and neck cancer

Since chemical compounds present in tobacco are inactivated by phase II enzymes, it has been proposed that head and neck cancer risk could be modified by NAT genotypes. Head and neck cancers are strongly associated with smoking, and a few studies have explored the role of NAT1 polymorphisms in the risk of developing head and neck cancer in smokers. However overall findings are inconsistent and associations if present are weak, and indicate either a decreased risk in carriers of the variant NAT1*10 (McKay et al., 2008), an increased risk (Katoh et al., 1998) or a lack of association (Fronhoffs et al., 2001; Henning et al., 1999; Agúndez, 2008).

Breast cancer

The NAT1*10 variant allele was associated to increased breast cancer risk among women who consumed well-done meat, although the statistical significance of this finding is low (Krajinovic et al., 2001). Several studies, however, indicate that no major association of NAT polymorphisms and breast cancer risk exists (Agúndez, 2008).

Colorectal cancer

A biologically plausible mechanistic hypothesis suggest that rapid NAT1 and/or NAT2 acetylators should more activate heterocyclic amine carcinogens within the colon to their ultimate carcinogenic forms, thereby predisposing them to colorectal cancer. However sufficient evidence is available to rule out a relevant association of NAT genotypes alone with colorectal cancer risk. This evidence is based in nearly thirty studies failed to detect a statistically significant association for NAT1 genotypes both with colorectal cancer or adenomas. In addition meta-analyses (Chen et al., 2005; Ye et al., 2002; Houlston et al., 2001) consistently confirm a lack of a relevant association of NAT1 rapid acetylator genotypes and colorectal cancer risk (revised in Agúndez, 2008).

Bladder cancer

No significant association of the NAT1 genotype with bladder cancer risk has been observed in a recent meta-analysis, although the authors found a joint effect of NAT1 rapid genotypes, slow NAT2 genotypes and smoking as factors increasing cancer risk (Sanderson et al., 2007). Overall findings are negative (Okkels et al., 1997), although a significant risk has been described in smokers (Taylor et al., 1998; Hsieh et al., 1999; Cascorbi et al., 2001) and a nearly significant association was observed in individuals exposed to benzidine (Carreon et al., 2006).