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Homozygous Rapid Arylamine N-Acetyltransferase (NAT2) Genotype as a Susceptibility Factor for Lung Cancer¹

Institute of Clinical Pharmacology, University Clinic Charité, Humboldt University of Berlin, Schumannstrasse 20/21, D-10098 Berlin [I. C., J. B., P. M. M., S. B., I. R.], and Department of Pneumology, Lungenklinik Heckeshorn, D-14109 Berlin [R. L.], Germany

The polymorphic arylamine N-acetyltransferase (NAT2) is supposed to be a susceptibility factor for certain malignancies. A phenotyping study in 389 lung cancer patients revealed a similar distribution of rapid and slow acetylators by the caffeine test to that in 657 reference subjects (odds ratio, 1.05; 95% confidence limits, 0.81, 1.36; not significant). A separate group of 155 lung cancer patients was studied by genotyping NAT2 and was compared with a matched reference group of 310 unrelated patients and with 278 healthy volunteers. The NAT2 genotype was characterized by PCR-RFLP at nucleotide positions 191, 282, 341, 481, 590, 803, and 857. For evaluation of nucleotide 341, a 3'-mismatch primer was used. Homozygous wild-type genotypes NAT2*4/*4 were confirmed by DNA sequencing. Genotypes for rapid acetylation amounted to 43.9% among lung cancer and 41.6% among reference patients (odds ratio, 1.10 95% confidence limits, 0.73, 1.65; not significant). Discrimination into homozygous and heterozygous carriers of allele NAT2*4 revealed a distinct overrepresentation of NAT2*4/*4 genotypes amid lung cancer patients (odds ratio, 2.36; 95% confidence limits, 1.05, 5.32; P = 0.018). Logistic regression analysis considering sex, age, and smoking provided an odds ratio of 3.04 (95% confidence limits, 1.37, 6.75; P = 0.003). Hence, carriers of the NAT2*4/*4 genotype, with its especially high acetylation capacity, are at significantly increased risk to lung cancer.

¹ This work was partly supported by a grant of the German Federal Ministry of Education, Science, Research and Technology (grant no. 01 EC 9408/0).

² To whom requests for reprints should be addressed. Phone: 49-30-2802-3635; Fax: 49-30-2802-5153; E-mail: cascorbi@rz.charite.hu-berlin.de.

Received 2/14/96. Accepted 7/ 2/96.

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