Lung cancer is the world's leading cause of cancer death with strong ancestry disparities. By sequencing and assembling the largest genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305) to date, we found that East Asian LUADs had more stable genomes characterized by fewer mutations and less copy number alteration than LUADs from individuals of European ancestry (EUR). This difference is much stronger in smokers as compared to non-smokers. Transcriptomic clustering identified a novel EAS-specific LUAD subgroup with a less complex genomic profile and up-regulated immune-related genes, allowing the possibility of immunotherapybased approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to the less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.
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