Genetic landscape features associated with PD-L1 expression status in advanced lung adenocarcinoma: a targeted sequencing analysis

Abstract

Background The tumor immune microenvironment influences non-small cell lung cancer (NSCLC) progression and therapy response. Programmed death-ligand 1 (PD-L1) is a key biomarker for immune checkpoint blockade, yet the genomic correlates of its expression status require elucidation. Methods We analyzed 97 advanced lung adenocarcinoma patients, (13 cases—all from the PD-L1-unknown subgroup—excluded due to insufficient sequencing quality, leaving 84 cases for downstream analyses) categorized by PD-L1 expression (positive: n=32; negative: n=45; unknown: n=20). Genomic profiling was performed using a 95-gene targeted NGS panel. Analyses included mutational profiling, pathway enrichment (GO/KEGG), gene interaction patterns, and genomic complexity. Results The cohort was predominantly metastatic (99.0%). Dominant mutations were in EGFR(43.80%), TP53(38.02%), and KRAS(11.57%). PD-L1-positive tumors more frequently harbored EGFRE746_A750del, while TP53 mutations were enriched in PD-L1-negative cases. Somatic interaction analysis revealed significant EGFR/TP53 co-occurrence in PD-L1-positive tumors and TP53/RB1 co-occurrence in negative tumors. GO analysis showed PD-L1-positive tumors were enriched for kinase-related functions, reflecting a distinct EGFR-driven biology characterized by a striking 59.26% prevalence of EGFR mutations. KEGG analysis indicated immune pathway enrichment in this subgroup, supporting an oncogene-induced immune phenotype frequently synergized by TP53 co-alterations. In contrast, PD-L1-negative tumors correlated with co-mutation-prone, metabolism-oriented profiles and immune suppression. Mutual exclusivity patterns differed: in PD-L1-positive tumors, EGFRmutations were mutually exclusive with KRAS/NRAS/HRASmutations, suggesting a single dominant driver. PD-L1-negative tumors displayed more co-occurring alterations (e.g., TP53 with STK11 or PTEN). Furthermore, 24% of PD-L1-positive tumors had multiple concurrent alterations, a proportion significantly higher than in PD-L1-negative tumors (8%; P<0.05). Conclusion This study delineates distinct genomic landscapes associated with PD-L1 expression. PD-L1-positive status is linked to an immune-active, kinase-signaling-driven phenotype with mutually exclusive drivers. PD-L1-negative status correlates with a more immunosuppressive, co-mutation-prone, and metabolism-oriented profile. These findings provide molecular insights into immune heterogeneity and may inform tailored combination therapies.