Lung cancer is the second most common cancer in the United States and the leading cause of cancer-related deaths. Significant disparities in incidence and outcome of lung cancer characterize the disease’s manifestation among ethnically and racially diverse populations. It has been found that Native Hawaiians (NH), Pacific Islanders (PI), and African Americans (AA) have the highest lung cancer risk and poorest survival outcomes compared to other populations. The influence of race and ethnicity is more evident at relatively low levels of smoking. After accounting for known lung cancer risk factors, NH and AAs remain at highest risk of lung cancer. The cause of these significant lung cancer health disparities is undoubtedly multifactorial. However, an unexplored factor is the molecular profiles of tumors arising in the NH/PI communities. In the past decade, large-scale lung cancer genomic studies have found clear racial disparity for lung cancer driver mutation genes. However, NHs have been strikingly underrepresented in The Cancer Genome Atlas Project (TCGA) and other cancer genome projects. There are almost no NH lung cancer patients included in the previous projects. There have also been no studies to compare DNA methylation changes between tumor and adjacent normal samples from NH/PI lung cancer patients, despite the importance of understanding how DNA methylation changes contribute to NH lung cancer development. To address the critical gap in lung cancer genomics studies and to understand the key factors that contribute to the health disparity of NH/PI lung cancer patients, we propose the following aims: 1. Characterize genomic landscape of lung cancer in NH patients. 2. Perform epigenomic profiling of lung cancer tissues in NH patients. 3. Identify NH specific genomic and epigenomic risk factors of lung cancer by comparing the profiles from NH with the published genomic and epigenomic data from other racial/ethnic populations. This project has the potential to be translated into improved lung cancer screening, precision prevention, and therapeutic intervention in NH and other populations. This project will also help us, via the Genomic Workforce Development Core included in the overall proposal, to train students, researchers, and community workers with genomics and genomic data science skills, such as whole genome sequencing (WGS), whole exome sequencing (WES), Illumina DNA methylation microarray, and whole-genome bisulfite sequencing (WGBS), as well as bioinformatics and data science skills related to the data analyses. The utility of these fundamental genomic technologies, is very useful for conducting biomedical research in any human diseases.