CYP1A1 and CYP1B1 Polymorphism and Lung Cancer Risk in Relation to Tobacco Smoking

Abstract

Background: The impact of genetic polymorphisms in CYP1A1 or CYP1B1 on susceptibility to lung cancer has received particular attention since these enzymes play a central role in the activation of major classes of tobacco carcinogens. Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. In the current German study, we investigated the role of CYP1A1 and CYP1B1 polymorphisms as a genetic modifier of risk for individuals with lung cancers as susceptible genotypes, especially in relation to tobacco smoking. Materials and Methods: Three polymorphisms, the CYP1A1 T6235C (CYP1A1 MspI), the CYP1A1 A4889G-position (CYP1A1 iva) as well as the CYP1B1 codon 432 polymorphism were determined by real-time PCR analysis in 446 lung cancer patients and in 622 controls. Results: The observed allele frequencies in the population were within the range described for Caucasians. Multivariate analyses of lung cancer patients, who carried at least one mutant variant allele of CYP1A1 T6235C (OR=1.06; 95%-CI: 0.7-1.6), CYP1A1 A4889G (OR=1.09; 95%-CI: 0.63-1.88) or CYP1B1 Val432Leu (OR=1.01 CI: 0.73-1.39) did not show any elevated risks. When analysed by histology, no individual subtype of lung cancer was significantly associated with the polymorphisms. Lung cancer risk rose significantly with higher cumulative cigarette consumption. Stratified analysis between tobacco smoking and variant genotypes revealed, for heavy smokers (>60 pack-years), increasing risks with the presence of at least one copy of the CYP1A1 T6235C variant allele OR=27.74 (95%-CI: 4.34-177.25), the CYP1A1 A4889G position OR=33.23 (95%-CI: 3.11-354.99) and the CYP1B1 OR=418.70 (95%-CI: 45.45-3856.89). By analysing the interaction between tobacco smoking and the genotypes, the combination of smoking and having the susceptible genotypes did not show a joint effect. Conclusion: In this study polymorphism of the CYP1A1 T6235C- or A4889G-position as well as CYP1B1-codon 432-polymorphisms had no relevant modifying effect on lung cancer risk and cumulative smoking dose.