The Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) network is a cancer moonshot inspired initiative between the National Cancer Institute, the Department of Defense, and the Department of Veterans Affairs to incorporate proteogenomics into patient care as a way of looking beyond the genome. The APOLLO Team, led by Dr. Matthew Wilkerson from Uniformed Services University of the Health Sciences, has just published a proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors in Cell Reports Medicine, that integrates whole-genome and transcriptome sequencing, mass spectrometry-based proteomics and phosphoproteomics, and reverse-phase protein arrays. Their findings, which include the identification and characterization of three distinct LUAD subtypes, provide a substantial foundation for future research.
As genomics and transcriptomics continue to provide insights into how patients will respond to therapy, tumor heterogeneity remains a key challenge in developing and implementing targeted therapies. This is especially true in cancers with a high degree of heterogeneity like LUAD which, despite recent advances in therapeutics, remains a leading cause of cancer deaths in the United States. The joint characterization of tumor proteomics with genomics and transcriptomics provides a deeper understanding of molecular mechanisms that drive tumor phenotypes and enables identification of proteome-specific markers and novel treatment paradigms. Using this strategy, the APOLLO network investigated how RNA and protein expression correlations are associated with tumor purity and immune cell profiles. Additionally, the team detected and validated RNA and protein expression signatures that accurately predict patient survival.
LUAD subtypes identified by somatic genome signature analysis were found to cluster by molecular etiologies and tobacco use. Two subtypes, referred to as transition-high and transversion-high, comprised never and current smokers, respectively, corresponding to somatic signature groups described in prior LUAD cohorts. Notably, the third subtype (referred to as structurally altered) revealed a bifurcation of smokers into a distinct group enriched in former smokers and characterized by structural genome disorganization, and TP53 alterations. A putative pathway of LUAD mutagenesis in the structurally altered subtype was hypothesized to involve a moderate transversion signature caused by limited exposure to tobacco mutagens and TP53 mutations that led to inhibition of DNA repair checkpoints which over time led to structural alterations being accumulated.
In summary, this body of work constitutes a great advancement in our understanding of LUAD. The approach taken by the APOLLO team highlights the potential of deep proteogenomic analysis to rigorously characterize tumors and, in turn, possibly discover more effective therapies. This publication complements existing CPTAC-LUAD cohort investigations, including a joint research effort with the International Cancer Proteogenome Consortium published in 2020.