Shared blood gene signature in lung adenocarcinoma and microbial lung infections: a bioinformatic analysis and in silico validation

Microbial lung infections may promote development of lung cancer through overlapping molecular mechanisms. This analysis aimed to identify a co-regulated peripheral blood gene signature in lung adenocarcinoma (LUAD) and microbial lung infections.

A total of 403 peripheral blood transcriptomic profiles from five GEO test datasets-two LUAD (GSE39345, GSE103527) and three infection-related (GSE40012, GSE65682, GSE103119)-were analyzed using the limma package. Differentially expressed genes (DEGs) were defined by|log₂FC| >1 and p < 0.05. Two additional GEO datasets (GSE42826 and GSE42830), comprising 30 blood samples (16 LUAD, 14 lung infection), served as validation sets. Shared DEGs were subjected to KEGG and GO enrichment analyses. Protein-protein interaction (PPI) networks were constructed in Cytoscape, and the top 10 hub genes were identified. Expression data of hub genes were compared between validation LUAD and lung infection samples using the Mann-Whitney U test, followed by linear regression and Pearson correlation to confirm co-regulation. Immune cell infiltration was assessed using xCell deconvolution algorithm.

Ninety-three significant DEGs were shared between LUAD and infection datasets, including 40 upregulated and 53 downregulated genes. Eight hub genes showed consistent differential expression in both LUAD and lung infection: BCL6, CD163, S100A12 (upregulated); and FLT3LG, RPL13, RPL14, RPL22, RPS4X (downregulated), of which BCL6, S100A12, FLT3LG, RPL13, RPL14, RPL22 and RPS4X were significantly co-regulated (R² >0.8, p < 0.001) and correlated (p < 0.05). Immune profiling revealed that upregulated genes were associated with immunosuppressive cells such as Tregs and M2 macrophages, while downregulated genes were positively correlated with antitumor immune cell infiltration including CD8⁺ T cells and M1 macrophages. Consistent immune, stroma and microenvironment scores were observed between LUAD and lung infection.

This analysis identified a blood-based 7-gene signature shared between LUAD and microbial lung infections, associated with immunosuppressive microenvironment features, suggesting a potential link between infection-driven inflammation and tumor-promoting immune modulation.