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

• DOI: 10.1016/j.xcrm.2022.100819
• Publication Date: 2022-11-16T05:02:28Z
• Authors: Anthony R. Soltis; Nicholas W. Bateman; Jianfang Liu; Trinh Nguyen; Teri J. Franks; Xijun Zhang; Clifton L. Dalgard; Coralie Viollet; Stella Somiari; Chunhua Yan; Karen Zeman; William J. Skinner; Jerry S.H. Lee; Harvey B. Pollard; Clesson Turner; Emanuel F. Petricoin; Daoud Meerzaman; Thomas P. Conrads; Hai Hu; Rebecca Blackwell; Gauthaman Sukumar; Dagmar Bacikova; Camille Alba; Elisa McGrath; Sraavya Polisetti; Meila Tuck; Alden Chiu; Gabe Peterson; Caroline Larson; Leonid Kvecher; Brenda Deyarmin; Jennifer Kane; Katie Miller; Kelly A. Conrads; Brian L. Hood; Sasha C. Makohon-...; Tamara S. Abulez; Elisa Baldelli; Mariaelena Pierobon; Qing-rong Chen; Henry Rodriguez; Sean E. Hanlon; Anthony R. Soltis; Nicholas W. Bateman; Jianfang Liu; Trinh Nguyen; Teri J. Franks; Xijun Zhang; Clifton L. Dalgard; Coralie Viollet; Stella Somiari; Chunhua Yan; Karen Zeman; William J. Skinner; Jerry S.H. Lee; Harvey B. Pollard; Clesson Turner; Emanuel F. Petricoin; Daoud Meerzaman; Thomas P. Conrads; Hai Hu; Craig D. Shriver; Christopher A. Mo...; Robert F. Browning; Matthew D. Wilkerson; Craig D. Shriver; Christopher A. Mo...; Robert F. Browning; Matthew D. Wilkerson
• Keywords: Proteomics; 0303 health sciences; 03 medical and health sciences; Lung Neoplasms; Humans; RNA; Adenocarcinoma of Lung; Article; Proteogenomics; 3. Good health

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.