ASSOCIATION OF THE NAT1-ASTERISK-10 GENOTYPE WITH INCREASED CHROMOSOME-ABERRATIONS AND HIGHER LUNG-CANCER RISK IN CIGARETTE SMOKERS

The NAT1 gene exhibits polymorphisms in the non-coding polyadenylation region with a number of alleles. Of these alleles, NAT1 10 is respon sible for increased NAT1 enzyme levels and is reported to be associate d with increased risk for colorectal and bladder cancers. In view of t he possible role of the NAT1 gene product in the metabolism of a numbe r of cigarette smoke carcinogens, we tested the possibility that genet ic variation in the NAT1 gene might also be associated with increased risk for lung cancer. Allelic variances of the NAT1 gene were analyzed in 45 lung cancer patients and 47 controls who were matched with resp ect to age, race and gender using restriction fragment length polymorp hism (RFLP) analysis and allele-specific CAS)-PCR. Our results indicat e that individuals who inherited the NAT110 allele had a 3.7-fold inc reased relative risk for lung cancer (95% CL = 1.2-16.0, p < 0.02). Th ere was a 6.8-fold increase in relative risk for lung cancer associate d with the inheritance of the NAT110 allele in younger individuals (< 60 years of age) compared to 2.2-fold increase in older individuals ( > 60 years old) (OR = 6.8; 95% CL = 1.1-40.7, p < 0.01 and OR = 2.2; 9 5% CL = 0.5-11.1, p = 0.2, respectively). We have also applied the sen sitive fluorescence in situ hybridization (FISH) tandem probe assay to elucidate the frequency of chromosome breakage among a subgroup of th e studied individuals harboring the NAT110 allele (17 lung cancer pat ients, 17 smoking controls and 7 non-smoking controls). Our results in dicate a significant increase (p < 0.001) in the frequency of chromoso me breaks in lung cancer patients (mean +/- SE per 100 cells = 1.45 +/ - 0.11) and in smoking controls (1.30 +/- 0.13) compared to non-smokin g controls (0.47 +/- 0.07). Regression analysis indicated a highly sig nificant positive correlation between the duration of smoking in years and the frequency of chromosome breaks in lung cancer patients (r = 0 .62, p = 0.008), but not in smoking controls (p = 0.02; p = 0.91). The se findings suggest that NAT1 polymorphism may be an important genetic determinant of lung cancer risk. In addition, these data provide a me chanistic link between the inheritance of the NAT1 10 allele and smok ing-induced lung cancer. Given that the NAT1 enzyme can mediate activa tion and detoxication pathways for numerous carcinogens and given that this polymorphism is prevalent in the general population (20-50% freq uency), it may play a significant role in influencing the outcome of a variety of environmental cancers. (C) 1998 Elsevier Science B.V.