Proteomics-based clustering of lung adenocarcinoma identifies three subtypes with significantly different clinical and molecular features.

Background: Lung adenocarcinoma (LUAD) is a predominant subtype of lung cancer. Although molecular classification of LUAD has been widely explored, proteomics-based subtyping of LUAD remains scarce.

Methods: We proposed a subtyping method for LUAD based on the expression profiles of 500 proteins with the largest expression variability across LUAD. Furthermore, we comprehensively compared molecular and clinical features among the LUAD subtypes.

Results: Consensus clustering identified three subtypes of LUAD, namely MtE, DrE, and StE. We demonstrated this subtyping method to be reproducible by analyzing two independent LUAD cohorts. MtE was characterized by high enrichment of metabolic pathways, high EGFR mutation rate, low stemness, proliferation, invasion, metastasis and inflammation signatures, favorable prognosis; DrE was characterized by high enrichment of DNA repair pathways, high TP53 mutation rate, and high levels of genomic instability, stemness, proliferation, and intratumor heterogeneity (ITH); and StE was characterized by high enrichment of stroma-related pathways, high KRAS mutation rate, and low levels of genomic instability.

Conclusions: The proteomics-based clustering analysis identified three LUAD subtypes with significantly different molecular and clinical properties. The novel subtyping method offers new perspectives on the cancer biology and holds promise in improving the clinical management of LUAD.