MECHANISMS OF ETHNIC/RACIAL DIFFERENCES IN LUNG CANCER SUSCEPTIBILTY EVALUATED WITH TOBACCO SMOKE TOXICANT AND CARCINOGEN BIOMARKERS AND GENETIC STUDIES

Stephen HECHT, University of Minnesota, United States
CARMELLA S. 1 , MURPHY S. 1 , PARK S. 3 , STRAM D. 2 , HAIMAN C. 2 , PATEL Y. 2 , LE MARCHAND L. 4

1 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
2 University of Southern California
3

Results of the Multiethnic Cohort Study demonstrated that African Americans and Native Hawaiians have a significantly higher risk for lung cancer than European Americans while Latinos and Japanese Americans have a significantly lower risk.  We are investigating the mechanistic basis for these remarkable differences with the expectation that the results will provide leads for identifying individuals highly susceptible to lung cancer.   We analyzed urine samples from 300-700 subjects per group for urinary total nicotine equivalents (the sum of nicotine and six metabolites comprising 80% of the nicotine dose), total NNAL (a biomarker of the powerful tobacco-specific lung carcinogen NNK), phenanthrene tetraol and 3-hydroxyphenanthrene (biomarkers of uptake and metabolism of carcinogenic PAH), and the mercapturic acids of acrolein, crotonaldehyde, and benzene (volatile toxicants and carcinogens in tobacco smoke).  The results demonstrated that African Americans, although smoking fewer cigarettes per day than any of the other groups except Latinos, had significantly higher levels of total nicotine equivalents, total NNAL, phenanthrene tetraol, 3-hydroxyphenanthrene, and the benzene metabolite S-phenylmercapturic acid compared to Whites while Japanese Americans had significantly lower levels of these biomarkers than Whites.  The relatively low levels of total nicotine equivalents in the urine of the Japanese American smokers was related to low activity polymorphisms in CYP2A6, the major enzyme responsible for nicotine metabolism.  The biomarker profiles of Native Hawaiians and Latinos did not fit this pattern, but Native Hawaiians had high levels of the acrolein biomarker compared to other groups while those of Latinos were low.  These results provide compelling new data pertinent to the relatively high risk of African Americans and the lower risk of Japanese Americans for lung cancer.  The results of this study may lead to new metrics for lung cancer susceptibility resulting in personalized approaches to smoking cessation and lung cancer prevention.