ABSTRACT We have shown in the Multiethnic Cohort (MEC) that Native Hawaiians have a markedly higher risk of lung cancer and a poorer survival from the disease compared to (non-Hispanic) Whites, even after accounting for smoking history and other risk/prognostic factors. This excess risk was observed for the two most common histologic cell-types: adenocarcinoma and squamous cell carcinoma as well as for small-cell lung cancer, a more aggressive cell-type. The poorer survival is observed with early stage and not advanced disease. We have made extensive efforts in the study of genetics, epigenetics and smoking and tobacco carcinogens-related biomarkers to understand the differences in lung cancer risk across populations. While the high risk in African Americans and low risk in Japanese Americans can be explained by higher and lower smoking intensity (carcinogens dose per cigarette), due to smoking behavior and lower nicotine metabolism, respectively, reasons for the risk excess in Native Hawaiians remain to be elucidated. Lung cancer screening using low-dose Computed Tomography (LDCT) among adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke, or have quit within the past 15 years, has been found to decrease mortality. However, the state of Hawaii ranks last in the proportion of lung cancers diagnosed at an early stage (19% vs. the national average of 24%), with less than 3% of high-risk smokers undergoing LDCT scan (national average is 6%). Studies have suggested that the use of risk-based prediction models may be more effective than the U.S. Preventive Services Task Force (USPSTF) criteria at identifying high-risk smokers for lung cancer screening. However, both the USPSTF guidelines and these risk prediction models were derived from data collected in mostly European-descent populations. We also found that there may be distinct biological processes related to tumorigenicity that contribute to the excess risk and poor disease outcomes for Native Hawaiians. We observed differences in epigenetic patterns in blood leukocyte DNA associated with smoking dose in Native Hawaiians when compared to other racial/ethnic groups, with the differential methylation occurring in cancer-related genes. To reduce the lung cancer burden of Native Hawaiians, we propose a multilevel translational study to identify the individual- and provider-based barriers for lung cancer screening to develop an intervention strategy to be disseminated in collaboration with the Hawaii Department of Health (Aim 1), to better identify those at greatest risk of developing lung cancer by computing a Native Hawaiian-specific risk prediction model (Aim 2), and to characterize the tumor pathobiology associated with the poor survival of Native Hawaiian lung cancer patients (Aim 3). Study findings will provide critical information along the continuum of lung cancer healthcare for a high risk minority population. During this grant cycle, we will develop collabor...