Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma. Display omitted •First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.