Sequence variants of NAT1 and NAT2 and other xenometabolic genes and risk of lung and aerodigestive tract cancers in Central Europe.
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.
McKay
James D
JD
Association for International Cancer Research, 150 cours Albert Thomas, Lyon Cedex 08, France. mckay@iarc.fr
Hashibe
Mia
M
Hung
Rayjean J
RJ
Wakefield
Jon
J
Gaborieau
Valerie
V
Szeszenia-Dabrowska
Neonila
N
Zaridze
David
D
Lissowska
Jolanta
J
Rudnai
Peter
P
Fabianova
Eleonora
E
Mates
Dana
D
Foretova
Lenka
L
Janout
Vladimir
V
Bencko
Vladimir
V
Chabrier
Amelie
A
Hall
Janet
J
Boffetta
Paolo
P
Canzian
Federico
F
Brennan
Paul
P
D000107:Acetylation; D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007390:International Agencies; D007527:Isoenzymes / Q000235:genetics*; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors
D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human