ABSTRACT
Many studies have been performed in an attempt to establish a link between the polymorphism of the cytochrome P450 CYP2D6 gene and the incidence of lung cancer. Nevertheless, whether or not this genetic polymorphism has a role in the development of the disease remains unclear. Recently, new advances in our knowledge of the CYP2D6 gene and its locus (CYP2D) have been achieved. In particular, CYP2D6 was found to be highly polymorphic and multiple novel mutations and allelic variants of the gene have been identified. In addition, a number of CYP2D rearrangements, including those with amplification of the gene, have been demonstrated. Taking this new information into account, we have reconsidered the potential influence of CYP2D6 polymorphism in lung cancer susceptibility by performing a comparative analysis of the overall mutational spectrum of CYP2D6 and of the rearrangements of CYP2D in 249 patients with lung cancer and in 265 control individuals matched on age, sex, hospital and residence area. For this purpose, a strategy based on SSCP analysis of the entire coding sequence of CYP2D6 and on RFLP analysis of the gene locus was carried out in DNA samples from each individual. Forty mutations occurring in various combinations on 42 alleles of the gene and 82 different genotypes were identified. No significant difference in the distribution of the mutations, alleles or genotypes was observed between the two groups, except a particular genotype (CYP2D6*1A/*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 genotype, only a trend toward a higher frequency of ultrarapid metabolizers in patients was obtained. In spite of a complete analysis of the CYP2D6 gene and its locus, this case-control study provides elements against an influence of the CYP2D6 polymorphism on lung cancer susceptibility.
Subject(s)
Cytochrome P-450 CYP2D6/genetics , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Polymorphism, Genetic , Alleles , Case-Control Studies , Cytochrome P-450 CYP2D6/metabolism , France/epidemiology , Gene Frequency , Gene Rearrangement , Genotype , Humans , Lung Neoplasms/epidemiology , Male , Multigene Family , Mutation , Phenotype , Polymorphism, Restriction Fragment Length , Polymorphism, Single-Stranded Conformational , White People/geneticsABSTRACT
The cytochrome P450 CYP2D6 gene (CYP2D6) expression was examined in samples from human bronchial mucosa and lung parenchyma using reverse transcription-polymerase chain reaction (RT-PCR) and immunochemistry. Except specimen from a patient previously genotyped as homozygous for a complete deletion of the gene, all tissue samples were positive. When compared to that in the liver, the mean level of CYP2D6 mRNA was 3-fold lower in bronchial mucosa and 6-fold lower in lung parenchyma. To our knowledge, these data demonstrate for the first time the presence of CYP2D6 protein in human lung. They also indicate that the gene is nonuniformly distributed within this organ. The possibility that CYP2D6 has a role in lung carcinogenesis by locally activating inhaled chemicals should therefore be considered.
