Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD. [Display omitted] •Lung adenocarcinoma has three subtypes defined by genome alteration profiles•Tumors with greater immune content have reduced RNA:protein correlation•Protein and RNA signatures predicting survival of patients are identified•Phosphoproteomic networks identify potential therapeutic vulnerabilities among subtypes Soltis et al. report a proteogenomic characterization of lung adenocarcinoma from the United States, expanding the disease’s etiology with a structurally altered subtype and connecting expression correlations between RNA and protein to tumor immune content. Integrative analysis reveals signatures of patient survival and targets for therapeutic intervention among molecular subtypes.