Background: Chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma are common causes of death worldwide. COPD can increase the risk of lung cancer, but genetic analysis between COPD and lung adenocarcinoma is still limited. The purpose of this study is to explore susceptible genes between COPD with or without lung adenocarcinoma. Methods: Using the published data of GSE106899, a co-expression module was constructed by weighted gene co-expression network analysis(WGCNA)to study COPD with lung adenocarcinoma. The most related module row function enrichment analysis and protein network analysis were selected, and the hub gene was found according to the intramuscular connectivity between the top 50 genes in the module and the connectivity in the protein network. The authenticity of hub genes was verified by immunohistochemical analysis of lung tissues of patients with COPD and COPD with lung adenocarcinoma. Results: Twenty co-expression modules were constructed from 13865 genes from 62 patients of COPD with lung adenocarcinoma. The protein-protein network and intramuscular connectivity showed that MTA1, PKMYT1 and FZR1 genes had the most connectivity, which were found to be most relevant to tumor progressions, mainly enriched in cell cycle, DNA transcription and replication and cancer pathways. Compared with COPD, the overexpression of MTA1, PKMYT1 and FZR1 genes in lung tissues of COPD with lung adenocarcinoma was validated by immunohistochemical analysis. Conclusions: This study suggests MTA1, PKMYT1 and FZR1 genes may play important roles in the progression of COPD with lung adenocarcinoma.