CYTOCHROME-P450 CYP2D6 GENE POLYMORPHISM AND LUNG-CANCER SUSCEPTIBILITY IN CAUCASIANS

Many studies have been performed in an attempt to establish a link bet ween the polymorphism of the cytochrome P450 CYP2D6 gene and the incid ence of lung cancer. Nevertheless, whether or not this genetic polymor phism has a role in the development of the disease remains unclear. Re cently, new advances in our knowledge of the CYP2D6 gene and its locus (CYP2D) have been achieved. In particular, CYP2D6 was found to be hig hly polymorphic and multiple novel mutations and allelic variants of t he gene have been identified. In addition, a number of CYP2D rearrange ments, including those with amplification of the gene, have been demon strated. Taking this new information into account, we have reconsidere d the potential influence of CYP2D6 polymorphism in lung cancer suscep tibility by performing a comparative analysis of the overall mutationa l spectrum of CYP2D6 and of the rearrangements of CYP2D in 249 patient s with lung cancer and in 265 control individuals matched on age, sex, hospital and residence area. For this purpose, a strategy based on SS CP analysis of the entire coding sequence of CYP2D6 and on RFLP analys is of the gene locus was carried out in DNA samples from each individu al. Forty mutations occuring in various combinations on 42 alleles of the gene and 82 different genotypes were identified. No significant di fference in the distribution of the mutations, alleles or genotypes wa s observed between the two groups, except a particular genotype (CYP2D 61A/*2), which was more common in the sub-group of moderate smokers ( < 30 pack-years) suffering from small cell carcinoma (Odds Ratio (OR) 3.6, 95% CI 1.1-11.9). When the phenotype was predicted according to g enotype, only a trend toward a higher frequency of ultrarapid metaboli zers in patients was obtained. In spite of a complete analysis of the CYP2D6 gene and its locus, this case-control study provides elements a gainst an influence of the CYP2D6 polymorphism on lung cancer suscepti bility. (C) 1998 Chapman & Hall Ltd.