POLYMORPHISMS IN THE HUMAN CYP1A1 GENE AS SUSCEPTIBILITY FACTORS FOR LUNG-CANCER - EXON-7 MUTATION (4889 A TO G), AND A T TO C MUTATION IN THE 3'-FLANKING REGION

Genetic differences in the metabolism of carcinogens may codetermine i ndividual predisposition to cancer. Cytochrome P-4501A1 (CYP1A1) metab olically activates precarcinogens in cigarette smoke, such as benzo(a) pyrene, which is also an inducer of CYP1A1. Two point mutations have b een reported, mi in the 3'-flanking region (6235T to C), and m2 within exon 7 (4889A to G), the latter leading to an isoleucine to valine ex change. In the Japanese population mi and m2 are correlated with lung cancer, suggesting an increased susceptibility to cigarette smoking re lated lung cancer. We studied 142 lung cancer and 171 reference patien ts in an ethnically homogeneous German group for mi and m2 mutations b y restriction fragment length polymorphism and allele-specific polymer ase chain reaction, respectively. No statistically significant differe nce was found in the distribution of m1 alleles between lung cancer an d controls; the frequency was 8.5% and 7.3% of the alleles, respective ly (odds ratio = 1.17). A trend to an overrepresentation of m1 alleles was observed among 52 squamous cell carcinoma patients (odds ratio = 1.65). In contrast, the frequency of m2 alleles in lung cancer patient s was twofold higher (6.7%) than in the reference group (3.2%; odds ra tio = 2.16; 95% confidence limits 0.96-5.11, P = 0.033); the odds rati o of m2 alleles in squamous cell carcinoma was 2.51 (95% confidence li mits 0.85-7.05, P = 0.05). There was a close genetic linkage of m2 to mi (10 of 11 reference patients), but a significantly higher number of cancer patients showed no linkage compared to the controls (odds rati o 8.89, 95% confidence limits 0.83-433, P = 0.04). Thus no association was found between presence of m1 alleles and lung cancer, but, in con trast, m2 alleles proved as a hereditary risk factor, especially if no t linked with m1 alleles.