Lung cancer is the leading cause of mortality worldwide. Although tobacco control is the best method for preventing this disease, there is little indication that smoking rates will decrease much further in the U.S. We documented that there exist 2-to-5-fold differences among US racial/ethnic minorities in the risk of lung cancer associated with cigarette smoking, even after taking into account self-reported dose (cigarettes per day) and duration. Native Hawaiians and African Americans have a significantly higher risk for lung cancer than European Americans, who in turn have a significantly higher risk than Japanese Americans and Latinos. We hypothesize that these differences are related to common genetic variants that affect internal dose and metabolism of nicotine and tobacco smoke carcinogens, and/or DNA repair. Our preliminary data obtained collaboratively with the laboratory investigators on this POI suggest that a combination of genetic and behavioral factors acting on several metabolic and/or DNA repair pathways are likely to explain the observed ethnic differences in risk. We propose to conduct a genome-wide association study (GWAS) to comprehensively assess the role of genetic variation in predicting 11 biomarker phenotypes (measured by Core B) related to tobacco carcinogen and nicotine exposure and metabolism among 2,250 Native Hawaiian, African American, European American, Latino and Japanese American smokers in the Multiethnic Cohort study, using stored biospecimens. We expect common inherited variation to assist in better assessing one's actual exposure level (as compared to cigarettes/day) and ability to metabolize tobacco carcinogens and, thus, in better predicting risk of developing lung cancer. We also expect the underlying causal variants to be more common in ethnic/racial populations at high risk for lung cancer. Finally, as part of this project, we will test the genetic variants associated with these phenotypes, as well as variants in DNA repair genes, for association with lung cancer incidence among 1,448 incident cases and 1,448 matched controls ofthe same five ethnic groups in the MEC. The results of these studies will provide important information on the biological determinants of internal dose and metabolism of nicotine and tobacco carcinogens and their relationships to lung cancer risk in U.S. ethnic/racial minorities.

Public Health Relevance

Lung cancer is the leading cause of cancer deaths worldwide. We have shown that African Americans and Native Hawaiians have lung cancer risks that are 2-5 times higher than other ethnic/racial groups in the U.S. This study will examine the common genetic factors that affect how people smoke and respond to tobacco smoke carcinogens. This may lead to better smoking cessation and lung cancer prevention methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA138338-05
Application #
8637000
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$943,323
Indirect Cost
$398,719
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Patel, Yesha M; Park, Sunghim L; Han, Younghun et al. (2016) Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk. Cancer Res 76:5768-5776
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
Kotapati, Srikanth; Esades, Amanda; Matter, Brock et al. (2015) High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation. Chem Biol Interact 241:23-31
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
Kotandeniya, Delshanee; Carmella, Steven G; Ming, Xun et al. (2015) Combined analysis of the tobacco metabolites cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in human urine. Anal Chem 87:1514-7
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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