Abstract
Results from the Multiethnic Cohort Study demonstrated significant differences in lung cancer risk among cigarette smokers from five different ethnic/racial groups. For the same number of cigarettes smoked, and particularly among light smokers, African Americans and Native Hawaiians had the highest risk for lung cancer, Whites had intermediate risk, while Latinos and Japanese Americans had the lowest risk. We analyzed urine samples from 331–709 participants from each ethnic group in this study for metabolites of phenanthrene, a surrogate for carcinogenic polycyclic aromatic hydrocarbon exposure. Consistent with their lung cancer risk and our previous studies of several other carcinogens and toxicants of cigarette smoke, African Americans had significantly (p<0.0001) higher median levels of the two phenanthrene metabolites 3-hydroxyphenanthrene (3-PheOH, 0.931 pmol/ml) and phenanthrene tetraol (PheT, 1.13 pmol/ml) than Whites (3-PheOH, 0.697 pmol/ml; PheT, 0.853 pmol/ml) while Japanese-Americans had significantly (p = 0.002) lower levels of 3-PheOH (0.621 pmol/ml) than Whites. PheT levels (0.838 pmol/ml) in Japanese-Americans were not different from those of Whites. These results are mainly consistent with the lung cancer risk of these three groups, but the results for Native Hawaiians and Latinos were more complex. We also carried out a genome wide association study in search of factors that could influence PheT and 3-PheOH levels. Deletion of GSTT1 explained 2.2% of the variability in PheT, while the strongest association, rs5751777 (p = 1.8x10-62) in the GSTT2 gene, explained 7.7% of the variability in PheT. These GWAS results suggested a possible protective effect of lower GSTT1 copy number variants on the diol epoxide pathway, which was an unexpected result. Collectively, the results of this study provide further evidence that different patterns of cigarette smoking are responsible for the higher lung cancer risk of African Americans than of Whites and the lower lung cancer risk of Japanese Americans, while other factors appear to be involved in the differing risks of Native Hawaiians and Latinos.
Highlights
Lung cancer is the leading cause of cancer death in both men and women in the U.S, with more than 158,000 deaths in 2015, approximately 90% of which are caused by cigarette smoking [1]
We have analyzed urine samples from subjects in each ethnic group for metabolites of carcinogens and toxicants which are found in tobacco smoke and have carried out genome wide association studies (GWAS) in search of common genetic variants that might predict differences in levels of these metabolites [5,6,7,8]
The results to date demonstrate important differences in levels of metabolites of nicotine, the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone (NNK), acrolein, crotonaldehyde, and benzene among the ethnic groups which may contribute to the observed differences in lung cancer susceptibility in the Multiethnic Cohort (MEC) [5,6,7,8]
Summary
Lung cancer is the leading cause of cancer death in both men and women in the U.S, with more than 158,000 deaths in 2015, approximately 90% of which are caused by cigarette smoking [1]. We have analyzed urine samples from subjects in each ethnic group for metabolites of carcinogens and toxicants which are found in tobacco smoke and have carried out genome wide association studies (GWAS) in search of common genetic variants that might predict differences in levels of these metabolites [5,6,7,8]. The results to date demonstrate important differences in levels of metabolites of nicotine, the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone (NNK), acrolein, crotonaldehyde, and benzene among the ethnic groups which may contribute to the observed differences in lung cancer susceptibility in the MEC [5,6,7,8]. In the study reported here, we quantified 3-hydroxyphenanthrene (3-PheOH) and phenanthrene tetraol (PheT) (Fig 1) in the urine of smokers from the five different ethnic groups of the MEC, and carried out a GWAS to investigate genes associated with 3-PheOH and PheT levels in these smokers
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