Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention

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The tobacco-specific nitrosamine (TSNA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is considered a major contributor to the induction of lung cancer in smokers. The metabolism of NNK is complex with its carcinogenic effects likely via the formation of its major pro-carcinogenic metabolite, 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanol (NNAL). Two enantiomers of NNAL are formed: (R)- and (S)-NNAL, both of which are extensively detoxified by glucuronidation in humans. Our novel preliminary data demonstrate a strong and statistically significant inverse association between the ratio of urinary (R)-NNAL-glucuronide (Gluc)/(S)-NNAL- Gluc and lung cancer risk in two independent prospective cohort studies. Furthermore, smokers homozygous for the deletion polymorphism of the major NNAL-glucuronidating enzyme, UGT2B17, had a significant 3-fold higher risk for lung cancer than those with at least one functional UGT2B17 allele in both cohorts. These data strongly support our hypothesis that (R)-NNAL plays a key role in tobacco-induced lung carcinogenesis and suggests that we have identified novel important phenotypic and genetic markers of lung cancer risk. The goal of this proposal is to evaluate the importance of NNAL enantiomers and glucuronides in lung cancer carcinogenesis, and to elucidate novel phenotypic and genetic markers of NNAL formation and elimination pathways and lung cancer risk in multiple populations. Our goals are to prospectively evaluate whether the levels or ratios of specific urinary NNAL isomers or glucuronides are associated with lung cancer risk in: (1) Chinese smokers from three cohort studies from Shanghai and Singapore, and (2) White and Black smokers from the Southern Community Cohort Study, and to subsequently screen and validate genetic variants associated with the variability in NNAL enantiomer and glucuronide formation. These studies should provide crucial insight for understanding variability and establishing phenotypes and genotypes important in lung cancer risk and will assist in identifying smokers at high risk for lung cancer for the development of chemopreventive strategies targeting the NNK metabolism pathway.