Lung cancer is the leading cause of cancer death in both men and women. African Americans (AAs) have a higher risk of lung cancer than European Americans (EAs) and any other racial group in the U.S. In addition, socioeconomically disadvantaged populations suffer a higher burden of lung cancer than more We recently found that AA males living in deprived neighborhoods had up to a 1.5-fold increased risk of lung cancer than those living in better neighborhoods. We also found that healthy eating was associated with a lower risk of lung cancer. However, the biological mechanisms linking the DNA methylation, one of the most frequent and important epigenetic modifications, plays a crucial role in regulating gene expression and cell function. Lifestyle and socioeconomic status (SES) factors may affect health through methylation modifications AAs and affluent populations. socioeconomic factors with lung cancer is not clear. . In addition, SES disadvantaged populations endure a greater acceleration of biological aging. However, how the individual and social SES and lifestyle factors affect DNA methylation, biological aging, and lung cancer risk in AAs and socioeconomically disadvantaged populations is largely unknown. The ongoing NCI-funded Southern Community Cohort Study (SCCS), a landmark investigation tracking a cohort of ~86,000 adults, two-thirds AAs and one-third non-Hispanic EAs, shows a similar low SES among AAs and EAs. Building on these unique resources, we will conduct the first well-powered prospective social epigenomics study in a cohort at an elevated lung cancer risk. We will perform genome-wide methylation assays for pre-diagnostic blood samples from 1,250 incident lung cancer cases (800 AAs and 450 EAs) and 1,700 individually-matched controls (800 AAs and 900 EAs). Using these methylation data, along with rich epidemiological data collected in the SCCS, we will: identify methylation markers and patterns in association with race (self-reported and genetically determined), individual and social SES, and lifestyle factors (Aim 1) and further investigate whether DNA methylation markers and patterns identified in Aim 1 are associated with lung cancer risk (Aim 2); investigate the associations between lifestyle and SES factors with biological aging (methylation-based age and age acceleration) (Aim 3) and investigate whether biological aging is associated with lung cancer risk (Aim 4). We will further investigate the potential effect of SES and lifestyle factor changes on DNA methylation and biological aging. We will also conduct in vitro functional investigation of promising methylation sites and their regulated genes. Because detailed epidemiological data and biological samples have already been collected in the parent study, this proposed project is both highly feasible and extremely cost-efficient. Findings from this study may provide insights into how individual and social contextual factors affect DNA methylation and help us to better unde...