Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking

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ABSTRACT Lung cancer is the leading cause of cancer death in the U.S. This renewal application for years 11-15 of our Program Project Grant entitled “Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking” brings together our team of renowned experts in cancer molecular epidemiology, tobacco control, mechanisms and biochemistry of tobacco carcinogenesis, and biostatistics to continue our groundbreaking research on biochemical, molecular, and epigenetic mechanisms by which cigarette smoking causes lung cancer. We will build on our significant findings from ongoing studies which include important advances in the epigenetics of lung cancer, biochemistry of nicotine leading to addiction and cancer, DNA damage by tobacco smoke carcinogens including acrolein and 1,3-butadiene, and tobacco carcinogen biomarker studies which expand and explain the dramatic differences in lung cancer incidence among cigarette smokers from 5 ethnic groups – African Americans, Native Hawaiians, Whites, Latinos, and Japanese Americans. Project 1, “Genetic and epigenetic risk markers for lung cancer in former smokers” proposes to identify these markers of lung cancer risk in people who have quit smoking and improve our understanding of the ethnic/racial differences in lung cancer risk among former smokers. Project 2, “CYP2A6 genetic score, nicotine metabolism, and lung cancer” will focus on the primary catalyst of nicotine metabolism which is critical because people with low activity of this enzyme smoke fewer cigarettes and smoke those less intensely because they need less nicotine, which is proposed to lead to lower lung cancer risk. Project 3, “Untargeted adductomics to characterize ethnic differences in the exposome of smokers” hypothesizes that biological responses towards cigarette smoke exposure differ among individuals and ethnic groups due to genetic and/or epigenetic factors that lead to differences in metabolic and inflammatory responses to smoking. Project 4, “Carcinogenesis biomarkers in former smokers of the Multiethnic Cohort Study” will use a unique approach to determine the metabolic activation of polycyclic aromatic hydrocarbons as well as lipid peroxidation in the lungs of former smokers compared to never smokers. These 4 projects will be supported by 3 outstanding Cores: Administrative Core, Clinical and Biomarkers Core, and Biostatistics Core. Thus, our experienced investigators propose to continue their superb and unique teamwork to make significant progress in understanding lung cancer mechanisms among present and former cigarette smokers leading to new insights for prevention of fatal lung cancer.