This proposal brings together investigators with great expertise in tobacco carcinogenesis and genome wide association studies to investigate ethnic/ racial differences in lung cancer due to cigarette smoking. Among cigarette smokers, African Americans and Native Hawaiians have a higher risk, while Japanese Americans and Latinos have a lower risk for lung cancer than European Americans. We hypothesize that these differences in lung cancer susceptibility are due to ethnic and racial variations in exposure and response to cigarette smoke carcinogens. This hypothesis will be tested through a unique combination of genetic, biomarker, and mechanistic studies using innovative techniques and relying on superb internationally recognized expertise. If this hypothesis is supported, our mechanistic understanding of tobacco-induced lung cancer will increase immensely, thus providing important new insights for lung cancer prevention. Project 1, "Multiethnic Genome Scan of Metabolic Phenotypes" will examine the association of common genetic variants with phenotypic biomarkers of tobacco smoke constituent uptake and metabolic activation in different ethnic/racial groups. A genome wide association study of five ethnic/racial groups (450 subjects per group) will be carried out and the results integrated with those of tobacco smoke constituent biomarkers for nicotine and carcinogens. The highly integrated Projects 2-5 will collaborate with Project 1 and use the superb expertise of the project leaders to study the relevant mechanisms. Project 2, "Nicotine and NNK Glucuronidation Pathways in Smokers," will investigate ethnic differences in the metabolism of nicotine and the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), focusing on the crucial glucuronidation detoxification pathway. Project 3, "Ethnic/Racial Differences in 1,3-Butadiene Metabolism and DNA Adduct Formation," will focus on ethnic and racial differences in the metabolism of 1,3- butadiene. Project 4, "Ethnic/Racial Differences in DNA Repair," will investigate the critical role of DNA repair in protecting against mutagenicity and carcinogenicity of cigarette smoke carcinogens. Project 5, "Metabolism of NNK among African Americans," will directly test the hypothesis that there are ethnic and racial differences in the metabolism of the tobacco-specific lung carcinogen NNK. The projects will be supported by three Cores: A, Administrative;B, Tobacco Smoke Constituent Biomarker;and C, Biostatistics. The unique combination of expertise in this program project forms a powerful team arguably unmatched in its ability to address mechanisms of lung cancer development in smokers from different ethnic/racial groups.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-7 (O1))
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Johnson, Ronald L
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University of Minnesota Twin Cities
Schools of Medicine
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Patel, Yesha M; Stram, Daniel O; Wilkens, Lynne R et al. (2015) The contribution of common genetic variation to nicotine and cotinine glucuronidation in multiple ethnic/racial populations. Cancer Epidemiol Biomarkers Prev 24:119-27
Zarth, Adam T; Carmella, Steven G; Le, Chap T et al. (2014) Effect of cigarette smoking on urinary 2-hydroxypropylmercapturic acid, a metabolite of propylene oxide. J Chromatogr B Analyt Technol Biomed Life Sci 953-954:126-31
Kotapati, Srikanth; Sangaraju, Dewakar; Esades, Amanda et al. (2014) Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species. Carcinogenesis 35:1371-8
Park, Sungshim Lani; Kotapati, Srikanth; Wilkens, Lynne R et al. (2014) 1,3-Butadiene exposure and metabolism among Japanese American, Native Hawaiian, and White smokers. Cancer Epidemiol Biomarkers Prev 23:2240-9
Jing, Meng; Wang, Yaohua; Upadhyaya, Pramod et al. (2014) Liquid chromatography-electrospray ionization-tandem mass spectrometry quantitation of urinary [pyridine-D4]4-hydroxy-4-(3-pyridyl)butanoic acid, a biomarker of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation in smokers. Chem Res Toxicol 27:1547-55
Murphy, Sharon E; Park, Sung-Shim L; Thompson, Elizabeth F et al. (2014) Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups. Carcinogenesis 35:2526-33
Sangaraju, Dewakar; Villalta, Peter W; Wickramaratne, Susith et al. (2014) NanoLC/ESI+ HRMS3 quantitation of DNA adducts induced by 1,3-butadiene. J Am Soc Mass Spectrom 25:1124-35
Narayanapillai, Sreekanth C; Balbo, Silvia; Leitzman, Pablo et al. (2014) Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis 35:2365-72
Zhang, Jianqi; Stram, Daniel O (2014) The role of local ancestry adjustment in association studies using admixed populations. Genet Epidemiol 38:502-15
Carmella, Steven G; Ming, Xun; Olvera, Natalie et al. (2013) High throughput liquid and gas chromatography-tandem mass spectrometry assays for tobacco-specific nitrosamine and polycyclic aromatic hydrocarbon metabolites associated with lung cancer in smokers. Chem Res Toxicol 26:1209-17

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