Somatic mutation subtypes of lung adenocarcinoma in East Asian reveal divergent biological characteristics and therapeutic vulnerabilities

Summary: Lung adenocarcinoma (LUAD) patients in East Asia predominantly harbor oncogenic EGFR mutations. However, there remains a limited understanding of the biological characteristics and therapeutic vulnerabilities of the concurrent mutations of EGFR and other genes in LUAD. Here, we performed comprehensive bioinformatics analyses on 88 treatment-naïve East Asian LUAD patients. Based on somatic mutation clustering, we identified three somatic mutation subtypes: EGFR + TP53 co-mutation, EGFR mutation, and multiple-gene mutation. A proteogenomic analysis among subtypes revealed varying degrees of dysregulation in cell-cycle-related and immune-related processes. An immune-characteristic analysis revealed higher PDL1 protein expression in the EGFR + TP53 co-mutation subtype than in the EGFR mutation subtype, which may affect the therapeutic efficacy of anti-PD-L1 therapy. Moreover, integrating known and potential therapeutic target analysis reveals therapeutic vulnerabilities of specific subtypes and nominates candidate biomarkers for therapeutic intervention. This study provides new biological insight and therapeutic opportunities with respect to EGFR-mutant LUAD subtypes