Genome-wide DNA methylation profiling reveals body mass Index-dependent epigenetic signatures associated with lung cancer susceptibility.

[OBJECTIVE] This study aimed to investigate the association between body mass index (BMI)-related DNA methylation alterations and lung cancer risk.

[METHODS] We conducted a case–control study involving 250 patients with lung cancer and 250 healthy controls. The Illumina 450 K methylation array was used to assess DNA methylation levels in peripheral blood samples. Multivariate logistic regression analysis was performed. Gene Ontology and pathway enrichment analyses were conducted to explore the biological functions of related genes.

[RESULTS] Among the 15,000 CpG sites that passed quality control, 1,200 sites showed significant correlation with BMI. We identified 15 CpG sites as being significantly associated with lung cancer risk, with the most significant being hypermethylation of (cg00012345; odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.7–3.6) and hypomethylation of (cg04236487; OR = 1.8, 95%CI: 1.3–2.5). Moreover, BMI stratification analysis revealed stronger associations between DNA methylation and lung cancer risk in overweight and obese groups, with methylation showing increased risk in the overweight group (OR = 2.2, 95%CI: 1.6–3.0) and methylation in the obese group (OR = 1.8, 95%CI: 1.3–2.5). Pathway analysis identified significant enrichment in p53 signalling, MAPK signalling, apoptosis and immune response pathways ( < 0.05). The associations of and methylation with lung cancer risk were confirmed in two independent validation cohorts with similar effect sizes.

[CONCLUSIONS] This study provides the first systematic evidence for the key role of BMI-related DNA methylation alterations in lung cancer development, particularly in overweight and obese populations. Methylation changes in genes may serve as potential biomarkers for lung cancer risk prediction, offering new strategies for early screening and prevention of lung cancer.