Clinical Relevance of Somatic Mutations in Chinese Lung Adenocarcinoma and Their Prognostic Implications for Survival

Abstract

Abstract Background: To comprehensively elucidate the genomic and mutational features of LUAD, it is imperative to conduct ongoing investigations into the genomic landscape. In this study, we aim to analyze the somatic mutation profile and assessed the significance of these informative genes utilizing a retrospective LUAD cohort. Methods: A total of 247 Chinese samples were analyzed to exhibit the tumor somatic genomic alterations in patients with LUAD. The Cox regression analysis was employed to identify prognosis-related genes and establish a predictive model for stratifying patients with LUAD. Results: In the Dianjiang People's Hospital (DPH) cohort, the top five frequent mutated genes were EGFR (68%), TP53 (30%), RBM10 (13%), LRP1B (9%), and KRAS (9%). Of which, EGFR is a mostly altered driver gene and most mutation sites locate in tyrosine kinase regions. Oncogene pathway alteration and mutation signature analysis demonstrated the RTK-RAS pathway alteration and smoking were the main carcinogenic factors of the DPH cohort. Furthermore, we identified 34 driver genes in the DPH cohort, including EGFR (68%), TP53 (30.4%), RBM10 (12.6%), KRAS (8.5%), LRP1B (8.5%), and so on, and 45 Clinical Characteristic-Related Genes (CCRGs) were found to closely related to the clinical high-risk factors. We developed an MPGM risk model by integrating critical genes and oncogenic pathway alterations in LUAD patients from the DPH cohort. Based on publicly available LUAD datasets, we identified five genes, including BRCA2, ALK, BRAF, EGFR, and PDGFRA according to the multivariable Cox regression analysis. The MPGM-Low group showed significantly better overall survival (OS) compared to the MPGM-High group (P<0.0001, AUC=0.754). The robust performance was validated in 55 LUAD patients from the DPH cohort and another LUAD dataset. Immune characteristics analysis revealed a higher proportion of primarily DCs and mononuclear cells in the MPGM-Low risk group, while the MPGM-High risk group showed lower immune cells and higher tumor cell infiltration. Conclusions: This study provides a comprehensive genomic landscape of Chinese LUAD patients and developsan MPGM risk model for LUAD prognosis stratification. Further follow-up will be performed for the patients in the DPH cohort consistently to explore the resistance and prognosis genetic features.