Sequence Variants of NAT1 and NAT2 and Other Xenometabolic Genes and Risk of Lung and Aerodigestive Tract Cancers in Central Europe

Abstract

Tobacco smoke contains an extensive cocktail of highly carcinogenic chemicals. Individuals with a slower elimination rate of the chemicals in tobacco smoke may have increased exposure to their carcinogenic properties compared with those with a faster rate. Polymorphisms that alter the function of the genes involved in the activation or the detoxification of the chemical carcinogens in tobacco smoke can potentially influence an individual's risk of developing a tobaccorelated cancer. To test this hypothesis, we have genotyped polymorphisms in 16 genes involved in metabolism of chemical carcinogens in a Central and Eastern European case-control study comprising 2,250 lung cases, 811 upper aerodigestive cancer (UADT) cases, and 2,704 controls. The N-acetyltransferase (NAT) genes were the most implicated in risk, with the NAT1*10 haplotype showing an inverse association in lung cancer, in both heterozygote carriers [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.70-0.93] and homozygote carriers (OR, 0.70; 95% CI, 0.48-1.01), suggesting a genotype dose response (P < 0.001). In UADT cancer, a similar inverse association was noted in NAT1*10 although only in heterozygotes (OR, 0.78; 95%CI, 0.65-0.95). In NAT2, when considering the individuals inferred acetylator phenotypes based on their NAT2 diplotype, ''slow'' acetylators compared with intermediate or fast acetylators showed no association with risk. None of the other 14 genes provided robust evidence of an association for either lung or UADT cancer. We therefore conclude that, of the genetic variation studied, NAT1 gene was the most likely candidate to influence the risk of developing a tobacco-related cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):141 -7)

Polymorphisms of Human N-Acetyltransferases and Cancer Risk

“…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, but not of the NAT2 genotype, was identified [88]. In fact, although negative associations have been reported [89], NAT1 is emerging as the NAT gene most likely related to lung cancer [90].…”

NAT1 (N-acetyltransferase 1 (arylamine N-acetyltransferase))

“…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 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).…”

Interaction of environmental factors and genetic polymorphism in the etiology of cancer

“…Прак-тически во всех исследованиях, в которых была обна-ружена связь между риском развития рака мочевого пузыря и скоростью ацетилирования, показана досто-верная связь между аллельными вариантами NAT1 и NAT2 и риском развития рака мочевого пузыря [7], легкого [8] и опухолями верхних дыхательных и пи-щеварительных органов (ВДПО) [9]. Отметим, что в этих работах были исследованы большие выборки больных.…”

“…В частности, в эпидемиологическое иссле-дование J. D. McKey и соавт. были включены 2250 боль-ных раком легкого, 811 пациентов с раком ВДПО и 2700 лиц контрольной группы [9]. Проведено геноти-пирование нескольких групп генов I и II фаз метабо-лизма ксенобиотиков, из которых гены NAT1 и NAT2 оказались наиболее значимыми с точки зрения их вли-яния на риск развития злокачественных опухолей.…”