Sequence variants of NAT1 and NAT2 and other xenometabolic genes and risk of lung and aerodigestive tract cancers in Central Europe

James D. McKay, Mia Hashibe, Rayjean J. Hung, Jon Wakefield, Valerie Gaborieau, Neonila Szeszenia-Dabrowska, David Zaridze, Jolanta Lissowska, P. Rudnai, Eleonora Fabianova, Dana Mates, Lenka Foretova, Vladimir Janout, Vladimir Bencko, Amelie Chabrier, Janet Hall, Paolo Boffetta, Federico Canzian, Paul Brennan

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 tobacco-related 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.

Original languageEnglish
Pages (from-to)141-147
Number of pages7
JournalCancer Epidemiology Biomarkers and Prevention
Volume17
Issue number1
DOIs
Publication statusPublished - Jan 1 2008

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Tobacco
Lung
Genes
Neoplasms
Smoke
Odds Ratio
Heterozygote
Carcinogens
Confidence Intervals
Acetyltransferases
Homozygote
Haplotypes
Case-Control Studies
Lung Neoplasms
Genotype
Phenotype

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Sequence variants of NAT1 and NAT2 and other xenometabolic genes and risk of lung and aerodigestive tract cancers in Central Europe. / McKay, James D.; Hashibe, Mia; Hung, Rayjean J.; Wakefield, Jon; Gaborieau, Valerie; Szeszenia-Dabrowska, Neonila; Zaridze, David; Lissowska, Jolanta; Rudnai, P.; Fabianova, Eleonora; Mates, Dana; Foretova, Lenka; Janout, Vladimir; Bencko, Vladimir; Chabrier, Amelie; Hall, Janet; Boffetta, Paolo; Canzian, Federico; Brennan, Paul.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 17, No. 1, 01.01.2008, p. 141-147.

Research output: Contribution to journalArticle

McKay, JD, Hashibe, M, Hung, RJ, Wakefield, J, Gaborieau, V, Szeszenia-Dabrowska, N, Zaridze, D, Lissowska, J, Rudnai, P, Fabianova, E, Mates, D, Foretova, L, Janout, V, Bencko, V, Chabrier, A, Hall, J, Boffetta, P, Canzian, F & Brennan, P 2008, 'Sequence variants of NAT1 and NAT2 and other xenometabolic genes and risk of lung and aerodigestive tract cancers in Central Europe', Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 1, pp. 141-147. https://doi.org/10.1158/1055-9965.EPI-07-0553
McKay, James D. ; Hashibe, Mia ; Hung, Rayjean J. ; Wakefield, Jon ; Gaborieau, Valerie ; Szeszenia-Dabrowska, Neonila ; Zaridze, David ; Lissowska, Jolanta ; Rudnai, P. ; Fabianova, Eleonora ; Mates, Dana ; Foretova, Lenka ; Janout, Vladimir ; Bencko, Vladimir ; Chabrier, Amelie ; Hall, Janet ; Boffetta, Paolo ; Canzian, Federico ; Brennan, Paul. / Sequence variants of NAT1 and NAT2 and other xenometabolic genes and risk of lung and aerodigestive tract cancers in Central Europe. In: Cancer Epidemiology Biomarkers and Prevention. 2008 ; Vol. 17, No. 1. pp. 141-147.
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T1 - Sequence variants of NAT1 and NAT2 and other xenometabolic genes and risk of lung and aerodigestive tract cancers in Central Europe

AU - McKay, James D.

AU - Hashibe, Mia

AU - Hung, Rayjean J.

AU - Wakefield, Jon

AU - Gaborieau, Valerie

AU - Szeszenia-Dabrowska, Neonila

AU - Zaridze, David

AU - Lissowska, Jolanta

AU - Rudnai, P.

AU - Fabianova, Eleonora

AU - Mates, Dana

AU - Foretova, Lenka

AU - Janout, Vladimir

AU - Bencko, Vladimir

AU - Chabrier, Amelie

AU - Hall, Janet

AU - Boffetta, Paolo

AU - Canzian, Federico

AU - Brennan, Paul

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N2 - 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 tobacco-related 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.

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