Worldwide, lung cancer is the most common cancer and the leading cause of cancer-related deaths. While, cigarette smoking is the primary risk factor for this disease, only 15-20% of smokers will develop lung cancer. Moreover, we showed in the Multiethnic Cohort (MEC) Study that, on the average and for the same quantity of cigarette smoke, compared to whites, African Americans and Native Hawaiians have a 50% greater risk of developing lung cancer; whereas, Japanese Americans and Latinos have a 25% lower risk of the disease. In the prior funding period, we found that internal smoking dose, as measured by urinary total nicotine equivalents (TNE), was highest in African Americans and lower in Japanese Americans. This correlates with their population lung cancer risks. However, in Native Hawaiians and Latinos among biomarkers of internal smoking dose and tobacco toxicant exposure and metabolism, only the biomarkers for acrolein and crotoaldehyde correlated with directionality of lung cancer risk. Our preliminary DNA methylation data suggests that smoking dose may influence the epigenome differentially across racial/ethnic groups. Additionally, our preliminary analysis in MEC suggested that biomarkers of internal smoking dose over time (TNE-years) and of nicotine metabolism (cytochrome P450 2A6 activity) are associated with an increased risk of lung cancer, even after adjusting for self-reported measures of smoking dose (pack-years). The objectives of the proposed study are to identify biomarkers that are associated with smoking-related lung cancer risk and to improve our understanding of the mechanisms underlying the ethnic/racial differences in lung cancer risk. We propose to conduct an epigenome-wide association study of blood leukocyte DNA methylation with smoking dose and biomarkers of tobacco toxicant exposure and metabolism (Aim 1). We will also systematically investigate the association of biomarkers of tobacco toxicant exposure and metabolism (n=1,865 cases and 3,619 controls) and DNA methylation in blood leukocytes (n=1,600 cases and 3,354 controls) with lung cancer risk (Aim 2). Additionally, any biomarkers identified in the other projects (e.g. Projects 3 and 4: urinary DNA adducts of 1,3- butadiene, acrolein, and crotoaldehyde) that show a promise towards explaining the difference in disease risk will also be evaluated for potential associations with risk of lung cancer. We hypothesize that ethnic/racial and individual differences in lung cancer risk are due to disparate biological response to common tobacco lung toxicants, which will be reflected by variations in biomarkers of smoking dose, tobacco toxicant exposure and metabolism, and DNA methylation profiles. The findings from this study will expand our understanding of the smoking-related mechanisms of lung cancer and the ethnic/racial differences in lung cancer risk. The identification of risk biomarkers will aid in the development of novel smoking cessation interventions and targeted lung cancer screening efforts in high risk populations.

Public Health Relevance

Globally, lung cancer is the leading cause of cancer-related death; and while smoking is the primary risk factor for this disease, for the same quantity of cigarette smoked, lung cancer risk is markedly different across racial/ethnic groups. In order to explain the differences in disease risk, this projects seeks to identify epigenetic regions and biomarkers of tobacco toxicant exposure and metabolism that are associated with an increased risk of lung cancer. Findings from this study may lead to improvements in smoking cessation and lung cancer prevention methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA138338-08
Application #
9538592
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Murphy, Sharon E; von Weymarn, Linda B; Parenteau, Marc et al. (2018) Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N-glucuronide by African American Smokers. Chem Res Toxicol 31:168-175
Degner, Amanda; Carlsson, Henrik; Karlsson, Isabella et al. (2018) Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood. Chem Res Toxicol :
Park, Sungshim L; Patel, Yesha M; Loo, Lenora W M et al. (2018) Association of internal smoking dose with blood DNA methylation in three racial/ethnic populations. Clin Epigenetics 10:110
Murphy, Sharon E; Park, Sungshim Lani; Balbo, Silvia et al. (2018) Tobacco biomarkers and genetic/epigenetic analysis to investigate ethnic/racial differences in lung cancer risk among smokers. NPJ Precis Oncol 2:17
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
Park, Sungshim L; Murphy, Sharon E; Wilkens, Lynne R et al. (2017) Association of CYP2A6 activity with lung cancer incidence in smokers: The multiethnic cohort study. PLoS One 12:e0178435
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

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