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'Comparison of extremes' approach provides evidence against the modifying role of NAT2 polymorphism in lung cancer susceptibility.

Belogubova EV, Kuligina ESh, Togo AV, Karpova MB, Ulibina JM, Shutkin VA, Hanson KP, Popowski K, Mosyagin I, Cascorbi I, Hirvonen A, Imyanitov EN

Group of Molecular Diagnostics, N.N. Petrov Institute of Oncology, Pesochny-2, St-Petersburg 197758, Russian Federation.

NAT2 (arylamine N-acetyltransferase 2) polymorphism, being a key determinant of individual variations in acetylation capacity, is suspected to modify the risk of carcinogen-related malignancies. As tobacco smoke and other inhaled hazards contain a variety of NAT2 substrates, the relationship between NAT2 phenotype and lung cancer (LC) risk has been a subject of intensive research, however different case-control studies produced controversial data. In the present report, we employed a novel 'comparison of extremes' approach, i.e. we compared the distribution of NAT2 genotypes in lung cancer patients (LC, n=178) not only to the population controls (healthy donors (HD), n=364), but also to the subjects with a putative cancer-resistant constitution (elderly tumor-free smokers and non-smokers (ED), n=351). Frequencies of homozygous rapid, heterozygous rapid and slow acetylators were 6, 39 and 56% in LC, 8, 32 and 60% in HD, and 6, 35 and 59% in ED, respectively. Comparison of the NAT2 genotype frequencies between affected and non-affected individuals did not reveal any statistical deviations, irrespectively of smoking history, gender, age, or histological type of LC. Adjusted odds ratio for rapid vs. slow acetylators was 1.12 (95% confidence intervals (CI): 0.73-1.74) comparing LC vs. HD, and 1.10 (95% CI: 0.74-1.62) comparing LC vs. ED. Similar distribution of NAT2 acetylator genotypes both in tumor-prone and in tumor-resistant groups suggests that, despite the presence of NAT2 carcinogenic substrates in tobacco smoke, NAT2 polymorphism does not play a noticeable role in lung cancer susceptibility.

Published 5 April 2005 in Cancer Lett, 221(2): 177-83.
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