解析慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)合并肺癌共病患者的分子特征与核心通路，为共病精准诊疗提供理论依据。

从癌症基因组图谱数据库(the cancer genome atlas, TCGA)获取肺腺癌(lung adenocarcinoma, LUAD)和肺鳞癌(lung squamous cell carcinoma, LUSC)患者共375例基因表达数据及临床信息，筛选肺癌合并COPD 65例为合并COPD组，肺癌未合并COPD 310例为未合并COPD组。采用TPM标准化并log2(TPM＋1)转换，Limma算法(FDR<0.05)筛选差异表达基因(DEG)；行GO/KEGG富集分析；查询DEG在IRIS、ImmPort、Immunome、InnateDB、Reactome 5个免疫数据库中的收录及重叠情况。

两组年龄、性别、种族、肿瘤分期、其他癌症史差异无统计学意义；吸烟史和病理类型差异有统计学意义(P<0.05)。生存分析合并COPD组50例、未合并COPD组286例，剔除极端值(≤0 d)25例，删失比17.33%；调整性别、吸烟史、既往恶性肿瘤史和年龄前后，COPD状态与肺癌患者生存率无显著关联(调整前：HR＝1.069，P＝0.826；调整后：HR＝0.826，P＝0.560)，总生存期无显著差异(P＝0.5598)；375例中未合并COPD组死亡42例(13.55%)，合并COPD组死亡15例(23.08%)，P＝0.052，呈边缘统计学趋势。DEG筛选出140个差异转录本。KEGG富集显示：显著富集于5条通路(P<0.05)，包括PI3K/AKT信号通路(9个基因)、黏着斑(7个)、细胞外基质-受体相互作用(5个)、人乳头瘤病毒感染(9个)、肌细胞骨架(8个)；FGF1单独特异富集于PI3K/AKT信号通路；PDGFC富集于黏着斑与PI3K/AKT信号通路2条通路；PDGFRB富集于人乳头瘤病毒感染、黏着斑与PI3K/AKT信号通路3条通路；PDGFC、PDGFRB、LAMB2、ITGA10、COL6A2、COL9A2、COMP共7个基因同时富集于黏着斑与PI3K/AKT信号通路。GO富集显示：BP层面无显著富集差异；CC层面显著富集于细胞外基质(P＝1.3×10^－6)、含胶原细胞外基质(P＝2.6×10^－6)、细胞外区域(P＝2.0×10^－4，富集25个DEG，包括CCL17、PDGFC)；MF层面显著富集于胶原结合(P＝2.6×10^－5)、细胞外基质结构组成(P＝3.2×10^－5)。免疫数据库验证：去重后共收录46个DEG；CCL17同时被IRIS、ImmPort、Immunome、InnateDB 4个数据库收录；ETS1被3个数据库收录；LITAF、PDGFRB、ENTPD1各被3个数据库收录；C1QTFN1被2个数据库收录；40个基因仅被单一数据库收录。FGF1在合并COPD组中显著下调；PDGFC/PDGFRB显著高表达；CCL17差异表达(logFC＝－0.7862，P＝0.0014)。

PI3K/AKT信号通路及FGF1、PDGFC/PDGFRB、CCL17可能是COPD合并肺癌发生发展的潜在关键靶点，可为共病精准诊疗提供新思路。

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.