TP53 co-mutations are associated with elevated PD-L1 expression and high tumor mutational burden in non-small cell lung cancer: insights from comprehensive genomic profiling

Background: Precision oncology in non-small cell lung cancer (NSCLC) requires comprehensive genomic characterization to inform therapeutic decisions. However, the spectrum of genomic alterations and their co-mutation patterns, particularly in relation to immunotherapy biomarkers, remains incompletely understood. This study investigated the associations between driver gene alterations and clinicopathological characteristics, and characterized co-mutation patterns in relation to programmed cell death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) levels. Methods: We conducted a retrospective analysis of 431 NSCLC patients, utilizing a comprehensive pan-solid tumor next-generation sequencing (NGS) panel covering 654 genes to characterize genomic alterations. Clinicopathological characteristics were systematically collected and analyzed to identify significant differences across various mutational profiles. Systematic assessments were performed to evaluate interactions between co-mutations and PD-L1 expression as well as TMB. Results: Genomic profiling revealed EGFR as the most frequently mutated driver gene (59.1%), followed by TP53 (39.7%), RBM10 (14.6%), MUC16 (12.7%), and KRAS (10.0%). EGFR mutations showed a strong female predominance (P<0.001), whereas MUC16 (P=0.004) and KRAS (P<0.001) alterations were more common in males. TP53 (P=0.005) and KRAS (P<0.001) alterations were more frequently found in smokers. Patients with advanced disease stages exhibited higher frequencies of TP53 mutations (P<0.001), contrasting with the predominance of EGFR (P<0.001) and RBM10 (P=0.04) mutations in early-stage tumors. TP53 co-mutations were the most common types, especially TP53-EGFR and TP53-KRAS co-mutations. TP53-EGFR co-mutations had higher PD-L1 expression (P=0.03) and TMB level (P=0.03) than EGFR-only mutations. Patients with TP53-KRAS co-mutations showed significantly higher PD-L1 expression (P=0.01) and TMB level (P=0.01) than KRAS-only mutations. Conclusions: This study underscores the diverse genetic mutations occurring in NSCLC patients with varying risk factors. The identification of TP53 co-mutations provides critical insights for personalized immunotherapeutic strategies and optimizing treatment outcomes.