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Individual differences in lung cancer susceptibility in relation to polymorphisms of P-450IA1 gene and cigarette dose.

Individual differences in susceptibility to chemical carcinogens are one of the most important host factors in the development of human cancer. We studied the etiological association of lung cancer with the DNA polymorphisms of P-450 IA1 gene, because cytochrome P-450IA1 is responsible for the metabolic activation of benzo(a)pyrene and other procarcinogens in cigarette smoking to the ultimate forms in the initiation process of lung cancer. Three polymorphisms of the gene were identified by restriction fragment length polymorphisms (RFLPs) with Msp I: the predominant homozygous allele (A type), the heterozygote (B type), and the homozygous rare allele (C type). A comparison of genotype frequencies between patients with lung cancer and a healthy population revealed that the individuals with genotype C were at higher risk than other types, and that this genetic risk elevation was specific to the Kreyberg I type of the cancer with relative risk of 3.21 but not to the Kreyberg II. We further studied this genetic susceptibility to the squamous cell carcinoma of lung cancer in relation to cumulated cigarette smoking dose, and found that the genetically susceptible patients with genotype C contracted the cancer with less cigarette dose than other types. Our case-control study showed that the relative risk of genotype C was remarkably high at 7.31 with a low dose of cigarette consumption compared to genotypes A and B, and that risk elevation with increasing dose saturated at 13.17 at high dose levels where the risk of genotypes A and B was at 8.89.