N-acetyltransferase 2 (NAT2) gene polymorphisms in colon and lung cancer patients

Abstract

Background: N-acetyltransferase 2 (NAT2) metabolizes arylamines and hydrazines moeities found in many therapeutic drugs, chemicals and carcinogens. The gene encoding NAT2 is polymorphic, thus resulting in rapid or slow acetylator phenotypes. The acetylator status may, therefore, predispose drug-induced toxicities and cancer risks, such as bladder, colon and lung cancer. Indeed, some studies demonstrate a positive association between NAT2 rapid acetylator phenotype and colon cancer, but results are inconsistent. The role of NAT2 acetylation status in lung cancer is likewise unclear, in which both the rapid and slow acetylator genotypes have been associated with disease.

Methods: We investigated three genetic variations, c.481C>T, c.590G>A (p.R197Q) and c.857G>A (p.G286E), of the NAT2 gene, which are known to result in a slow acetylator phenotype. Using validated PCR-RFLP assays, we genotyped 243 healthy unrelated Caucasian control subjects, 92 colon and 67 lung cancer patients for these genetic variations. As there is a recent meta-analysis of NAT2 studies on colon cancer (unlike in lung cancer), we have also undertaken a systematic review of NAT2 studies on lung cancer, and we incorporated our results in a meta-analysis consisting of 16 studies, 3,865 lung cancer patients and 6,077 control subjects.

Results: We did not obtain statistically significant differences in NAT2 allele and genotype frequencies in colon cancer patients and control group. Certain genotypes, however, such as [c.590AA+c.857GA] and [c.590GA+c.857GA] were absent among the colon cancer patients. Similarly, allele frequencies in lung cancer patients and controls did not differ significantly. Nevertheless, there was a significant increase of genotypes [c.590GA] and [c.481CT+c.590GA], but absence of homozygous c.590AA and [c.590AA+c.857GA] in the lung cancer group. Meta-analysis of 16 NAT2 studies on lung cancer did not evidence an overall association of the rapid or slow acetylator status to lung cancer. Similarly, the summary odds ratios obtained with stratified meta-analysis based on ethnicity, and smoking status were not significant.

Conclusion: Our study failed to show an overall association of NAT2 genotypes to either colon or lung cancer risk.

Figure 1

Meta-analysis (Mantel-Haenszel, fixed effects) on 16 case-control association studies on NAT2 slow acetylator status and lung cancer. Test for heterogeneity χ² (df 15) = 25.58 (p = 0.0426). The summary odds ratio (OR = 1.04, 95% CI, 0.96–1.14) is not significant. Meta-analysis (DerSimonian-Laird, random effects) is similar, with summary OR (1.05, 95% CI 0.93–1.19, estimated random effects variance = 0.02), likewise not significant. The confidence interval for each study is given by a horizontal line, and the point estimate is given by a square whose height is inversely proportional to the standard error of the estimate. The summary odds ratio is drawn as a diamond with horizontal limits at the confidence limits and width inversely proportional to its standard error.

Figure 2

Meta-analysis (Mantel-Haenszel, fixed effects) on 13 case-control association studies on NAT2 slow acetylator status and lung cancer – Caucasians. Test for heterogeneity χ² (df 12) = 9.02 (p = 0.7012). The summary odds ratio (OR = 1.05, 95% CI, (0.96–1.15) is not significant.

Figure 3

Meta-analysis (Mantel-Haenszel, fixed effects) on 7 case-control association studies on NAT2 slow acetylator status and lung cancer – Caucasians, male smokers. The summary odds ratio (OR = 1.03 (95% CI, 0.9–1.18) is not significant.