GENETIC-POLYMORPHISM OF CYP2D6 AND LUNG-CANCER RISK IN AFRICAN-AMERICANS AND CAUCASIANS IN LOS-ANGELES-COUNTY

The well described genetic polymorphism of the CYP2Dd gene influences response to a wide variety of therapeutic agents metabolized by the CY P2D6 enzyme product, CYP2D6 also appears to play a role, along with ot her cytochrome P350 enzymes, in the metabolic activation of the tobacc o specific nitrosamine, NNK, as well as metabolism of nicotine to coti nine, While impaired activity of CYP2D6 was strongly protective agains t lung cancer in some studies, primarily based on phenotyping? the Lit erature is conflicting, The molecular basis of CYP2D6 deficiency is no w well understood, enabling the use of genotyping to classify individu als, We therefore examined whether lung cancer risk is reduced by the presence of four CYP2D6 alleles associated with impaired activity due to an inactivating mutation-CYP2D64, CYP2D6*3, CYP2D6*5 and CYP2D6*16 -among 341 incident cases of lung cancer and 710 population controls o f Caucasian or African-American ethnicity in Los Angeles County, Calif ornia, We did not confirm a strong association between the presence of these inactivating alleles and lung cancer risk [odds ratio (OR) = 0. 90, 95% confidence interval (CI) 0.60-1.35 for Caucasians], although t here was a small decreased risk among the African-Americans (OR = 0.66 , 95% CI 0.38-1.14), Among smokers, when the data are stratified accor ding to lifetime smoking history, there is a suggestion of an associat ion limited to Caucasian smokers of <35 pack-years, the median for all smokers in these data (OR 0.49, 95% CI 0.23-1.04), However, among Afr ican-American smokers, who smoke less than Caucasians, the association did not differ between smoking categories, We also examined the possi ble role of additional copies of the CYP2Dd gene, which lead to enhanc ed CYP2D6 activity, in increasing lung cancer risk, Among controls the prevalence of having more than two copies of the CYP2Dd gene and no i nactivating alleles was 4.3% for Caucasians and 4.9% for African-Ameri cans. Relative to subjects with an inactivating allele, those with an additional copy of the CYP2D6 gene and no inactivating alleles may be at increased risk of lung cancer, particularly for adenocarcinoma (OR = 3.61, 95% CI 1.08-11.7 for African-Americans and OR = 2.20, 95% CI 0 .69-6.0 for Caucasians), Our data suggest that the CYP2Dd genetic poly morphism is not the strong risk factor for lung cancer suggested by so me studies of phenotype, but may play a minor role.