GENETIC-POLYMORPHISM OF CYP2D6 AND LUNG-CANCER RISK

Previous reports of the association of extensive debrisoquine metaboli sm, controlled by the cytochrome P450 CYP2D6, with increased lung canc er risk have been conflicting, We examined the hypothesis that genetic polymorphism at the CYP2D6 locus identifies individuals at increased risk for lung cancer in a case-control study of 98 incident Caucasian lung cancer patients and 110 age-, race-, and sex-matched controls con ducted at the National Naval Medical Center, Bethesda, MD. Using germ line DNA, we identified inactivating mutations at the CYP2D6 locus (CY P2D63, CYP2D6*4, CYP2D6*5, and CYP2D6*6A), as well as those mutations that impair but do not abolish enzyme activity (CYP2D69 and CYP2D6*1 0A), Compared to subjects with homozygous inactivating mutations, no a ssociation with lung cancer was observed for those with homozygous or heterozygous functional alleles (odds ratios were 0.4 and 0.7, respect ively), Furthermore, no excess risk was seen in any histological group or smoking category, and adjustment for smoking and sociodemographic characteristics did not alter the findings, Although the concept that genetic polymorphisms may contribute to differential lung cancer susce ptibility is sound, these data do not support the role of CYP2D6 as a marker for elevated lung cancer risk.