Updated project metadata. To characterize the etiology of lung adenocarcinoma (LUAD) in the United States, we performed deep proteogenomic profiling of 87 tumors integrating whole genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry and reverse phase protein arrays. Somatic genome signature analysis revealed three subtypes including a structurally altered subtype enriched with former smokers, genomic inversions and deletions and TP53 alteration, a transition-high subtype enriched with never-smokers, and a transversion-high enriched with current smokers. We discovered that within-tumor correlations of RNA expression and protein expression were associated with tumor purity, grade, immune cell heterogeneity, and expression subtype. We detected and independently validated RNA and protein expression signatures predicting patient survival. A greater number of proteins than RNA transcripts had association with patient survival. Integrative analysis characterized three expression subtypes with divergent mutations, proteomic regulatory networks and therapeutic vulnerabilities. This proteogenomic characterization provides a new foundation for molecularly-informed medicine in LUAD.