ABSTRACT While smoking cessation efforts have resulted in a decrease in smoking and lung cancer rates, lung cancer remains the second most common cancer and the leading cause of cancer-related deaths for both men and women. Currently, at least half of the newly incident lung cancer cases are former smokers in the US. Moreover, there are racial/ethnic differences in smoking-related lung cancer risk; however, it is unclear of the extent these differences persist after smoking cessation. Low-dose CT screening for lung cancer has been shown to reduce lung cancer mortality by ~20%; however, screening recommendations are limited to current smokers and recent quitters (within 15 years) who were moderate or heavy smokers (≥20 pack-year smoking history), which does not address risk among those who have quit >15 years and/or who are light smokers. Prior genetic, epigenetic, and molecular marker studies have shown that differences in the frequencies or levels of these markers, may help to better understand risk differences across populations. Our data suggests that smoking may differentially influence DNA methylation levels across populations and that genetic, epigenetic, and biochemical markers of smoking may be associated with lung cancer risk in a multiethnic population independent of self-reported smoking data. The objective of this proposal is to improve the understanding of the mechanisms of lung cancer risk in a former smoker population. We propose to evaluate the impact of smoking cessation on lung cancer risk across five racial/ethnic groups from the Multiethnic Cohort study (MEC) with disparate risk of disease (Aim 1). We will conduct an epigenome-wide association study (EWAS) of years quit among former smokers from the MEC (Aim 2). Lastly, we will systematically investigate the association of genetic variants and DNA methylation from blood leukocytes and urinary cadmium levels (Aim 3) with risk of lung cancer. Additionally, we will interact with the other three projects in this P01 to study the influence of CYP2A6 genetic variants in relation to years quit (Project 2), the association of genetic variants with markers of the exposome (Project 3) and the association for urinary phenanthrene metabolite ratio with DNA methylation of AHRR (Project 4). We hypothesize that ethnic/racial and individual differences in lung cancer risk in former smokers are in part due to variations in genetics and different biological response to smoking cessation. The findings from this study will expand our understanding of risk and potential mechanisms for lung cancer in a multiethnic population of former smokers. This will help to identify for screening those individuals remaining at greatest risk of lung cancer despite them having taken the major step of quitting smoking to reduce their risk.