Molecular Links Between Smoking, COPD, and Lung Cancer: A DNA Methylation Perspective

Background: DNA methylation alterations represent a key epigenetic mechanism linking environmental exposures to disease pathogenesis. The present study aimed to identify differentially methylated genes and shared biological processes associated with lung cancer (LuCa), chronic obstructive pulmonary disease (COPD) and tobacco exposure. Methods: A comprehensive literature search was performed in PubMed to identify studies evaluating DNA methylation in LuCa, COPD and smoking-related models. A total of 117 articles were selected, including 83 studies on lung cancer, 18 on COPD and 16 on smoking exposure. Genes exhibiting statistically significant methylation changes relative to controls were extracted from each study. To provide additional support for these findings, differential methylation signatures were further evaluated using The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets. Functional and transcription factor motif enrichment analyses were subsequently conducted to identify shared biological pathways and regulatory mechanisms. Results: In total, 324 genes displaying altered methylation patterns across these conditions were identified. Seven tumor suppressor genes (CDKN2A, CDH13, MGMT, MIR137, DAPK1, RARB, and RASSF1A) consistently exhibited hypermethylation in both lung cancer and in association with smoking exposure. In addition, AHRR hypomethylation emerged as a shared epigenetic hallmark across all three conditions. TCGA-based analyses confirmed several of these methylation patterns and revealed subtype-specific methylation profiles associated with smoking history. Functional enrichment highlighted common biological processes and signaling pathways, particularly those related to transcriptional regulation, apoptosis and cancer-associated pathways. Conclusions: These results provide an integrative overview of shared DNA methylation alterations associated with smoking exposure, COPD, and lung cancer, and suggest potential DNA methylation candidates that may be relevant for future biomarker development and mechanistic studies.