Lung cancer is the leading cause of cancer mortality in the U.S. and woridwide with the majority of these cancers caused by smoking. The Multiethnic Cohort (MEC) study strongly demonstrated that there are major differences among US ethnic/racial groups in lung cancer risk associated with smoking. We will investigate the hypothesis that African Americans are more susceptible to the carcinogenic properties of tobacco-associated chemicals than European Americans as a result of reduced DNA repair capacity. This will be assessed by determining the sensitivity of lymphocytes from Africans or African Americans and European Americans to the toxic and mutagenic activity of activated forms ofthe three tobacco carcinogens, 4 (methylnitrosamino)-l-(S pyridyl)-1 butanone, benzo[a]pyrene and 1,S-butadiene. We will test our hypothesis by performing the following specific aims: 1. Determine if there is a difference in sensitivity between European Americans and Africans to the cytotoxic effects of activated tobacco smoke carcinogens using the International HapMap Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines derived from trios of European Americans (CEU) and Yoruban (African, YRI) populations;2. Determine if there is a difference in sensitivity between European Americans and Africans to the genotoxic effects of activated tobacco smoke carcinogens using the HapMap B-lymphocyte cell lines;3. Determine if there is a difference in repair rates for tobacco smoke-derived carcinogen DNA adducts between European Americans and Africans using the HapMap lymphocyte cell lines or lymphocytes isolated from European American and African American smokers in Project 5;4. Perform candidate gene and genome-wide association studies of the toxicological phenotypes measured in Aims 1-3 to determine if specific genotypes drive the observed phenotypes in collaboration with Project 1. Collectively, these studies will reveal if there are ethnic/racial differences in repair of tobacco carcinogen derived DNA damage and if these differences in repair translate into differences in sensitivity to the genotoxic effects of these chemicals.
DNA repair is a critical step in the protection of a cell against the genotoxic effects of tobacco-carcinogens. Genetic variations in the proteins involved in these multiple step process influence how a cell responds to a gentoxic insult. Characterization genetic variations responsible for this decreased risk will allow for the identification of at risk individuals and allow the development of eariy detection and prevention strategies.
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|Park, Sungshim L; Tiirikainen, Maarit I; Patel, Yesha M et al. (2016) Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risks of lung cancer and effect on their smoking intensity. Carcinogenesis 37:269-79|
|Ma, Bin; Ruszczak, Chris; Jain, Vipin et al. (2016) Optimized Liquid Chromatography Nanoelectrospray-High-Resolution Tandem Mass Spectrometry Method for the Analysis of 4-Hydroxy-1-(3-pyridyl)-1-butanone-Releasing DNA Adducts in Human Oral Cells. Chem Res Toxicol 29:1849-1856|
|Zanetti, Krista A; Wang, Zhaoming; Aldrich, Melinda et al. (2016) Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population. Lung Cancer 98:33-42|
|Patel, Yesha M; Park, Sungshim L; Carmella, Steven G et al. (2016) Metabolites of the Polycyclic Aromatic Hydrocarbon Phenanthrene in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer. PLoS One 11:e0156203|
|Haiman, Christopher A; Patel, Yesha M; Stram, Daniel O et al. (2016) Benzene Uptake and Glutathione S-transferase T1 Status as Determinants of S-Phenylmercapturic Acid in Cigarette Smokers in the Multiethnic Cohort. PLoS One 11:e0150641|
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|Zarth, Adam T; Murphy, Sharon E; Hecht, Stephen S (2015) Benzene oxide is a substrate for glutathione S-transferases. Chem Biol Interact 242:390-5|
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|Park, Sungshim L; Carmella, Steven G; Ming, Xun et al. (2015) Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. Cancer Epidemiol Biomarkers Prev 24:561-9|
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