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.
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.
|Chai, Weiwen; Morimoto, Yukiko; Cooney, Robert V et al. (2017) Dietary Red and Processed Meat Intake and Markers of Adiposity and Inflammation: The Multiethnic Cohort Study. J Am Coll Nutr 36:378-385|
|Murphy, Sharon E (2017) Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chem Res Toxicol 30:410-419|
|Boldry, Emily J; Patel, Yesha M; Kotapati, Srikanth et al. (2017) Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer. Cancer Epidemiol Biomarkers Prev 26:1034-1042|
|Sangaraju, Dewakar; Boldry, Emily J; Patel, Yesha M et al. (2017) Isotope Dilution nanoLC/ESI+-HRMS3 Quantitation of Urinary N7-(1-Hydroxy-3-buten-2-yl) Guanine Adducts in Humans and Their Use as Biomarkers of Exposure to 1,3-Butadiene. Chem Res Toxicol 30:678-688|
|Peterson, Lisa A (2017) Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK. Chem Res Toxicol 30:420-433|
|Hecht, Stephen S (2017) Oral Cell DNA Adducts as Potential Biomarkers for Lung Cancer Susceptibility in Cigarette Smokers. Chem Res Toxicol 30:367-375|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 40 publications