To elucidate the molecular characteristics and core pathways of chronic obstructive pulmonary disease(COPD) in lung cancer patients, thereby providing a theoretical basis for precision diagnosis and treatment of this comorbidity.

Gene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) database for a total of 375 patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Of these, 65 patients with lung cancer and comorbid COPD constituted the COPD-comorbid group, and 310 patients with lung cancer without COPD constituted the non-COPD group. differentially expressed genes (DEGs) were identified using the Limma algorithm (FDR<0.05) after TPM normalization and log transformation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed to identify biological pathways related to COPD, and the inclusion of the DEGs in, and their overlap across, five immunological databases (IRIS, ImmPort, Immunome, InnateDB, and Reactome) were used to distinguish immunological-related DEGs.

No statistically significant differences were observed between the two groups in age, sex, race, tumor stage, or history of other cancers, whereas smoking history and pathological type differed significantly (P<0.05). Survival analysis included 50 patients in the COPD-comorbid group and 286 patients in the non-COPD group; after exclusion of 25 patients with extreme values (≤0 d), the censoring rate was 17.33%. Both before and after adjustment for sex, smoking history, history of prior malignancy, and age, COPD status was not significantly associated with survival in patients with lung cancer (unadjusted: HR=1.069, P=0.826; adjusted: HR=0.826, P=0.560), and overall survival did not differ significantly (P=0.5598). Among the 375 patients, 42 deaths (13.55%) occurred in the non-COPD group and 15 deaths (23.08%) in the COPD-comorbid group (P=0.052), indicating a borderline statistical trend. DEG screening identified 140 differentially expressed transcripts. KEGG enrichment analysis showed significant enrichment in five pathways (P<0.05), namely the PI3K/AKT signaling pathway (9 genes), focal adhesion (7 genes), extracellular matrix (ECM)-receptor interaction (5 genes), human papillomavirus infection (9 genes), and regulation of the actin cytoskeleton (8 genes). FGF1 was uniquely and specifically enriched in the PI3K/AKT signaling pathway; PDGFC was enriched in two pathways, focal adhesion and the PI3K/AKT signaling pathway; PDGFRB was enriched in three pathways, human papillomavirus infection, focal adhesion, and the PI3K/AKT signaling pathway; and a total of seven genes-PDGFC, PDGFRB, LAMB2, ITGA10, COL6A2, COL9A2, and COMP -were simultaneously enriched in both focal adhesion and the PI3K/AKT signaling pathway. GO enrichment analysis showed no significant enrichment at the biological process (BP) level; at the cellular component (CC) level, significant enrichment was observed in the extracellular matrix (P=1.3×10^-6), collagen-containing extracellular matrix (P=2.6×10^-6), and extracellular region (P=2.0×10^-4, with 25 DEGs enriched, including CCL17 and PDGFC); and at the molecular function (MF) level, significant enrichment was observed in collagen binding (P=2.6×10^-5) and extracellular matrix structural constituent (P=3.2×10^-5). By checking immunological databases, a total of 46 DEGs were recorded: CCL17 was simultaneously recorded in four databases (IRIS, ImmPort, Immunome, and InnateDB); ETS1 was recorded in three databases; LITAF, PDGFRB, and ENTPD1 were each recorded in three databases; C1QTFN1 was recorded in two databases; and 40 genes were recorded in only a single database. FGF1 was significantly downregulated in the COPD-comorbid group; PDGFC/PDGFRB were significantly overexpressed; and CCL17 was differentially expressed (log2FC=-0.7862, P=0.0014).

The PI3K/AKT signaling pathway, together with FGF1, PDGFC/PDGFRB, and CCL17, may represent potential key targets in the development and progression of COPD comorbid with lung cancer, offering new insights for the precision diagnosis and treatment of this comorbidity.