DNA Methylation Analysis Identifies Clinically Relevant Lung Adenocarcinoma Subgroups

Abstract Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and is characterized by significant molecular heterogeneity and poor prognosis, primarily due to late-stage diagnoses. Therefore, detailed molecular characterization of LUAD is crucial for developing biomarkers to accurately detect the disease in its early stages. This study investigates the role of DNA methylation in LUAD, emphasizing its potential as a biomarker for cancer detection and as a tool for understanding tumor biology. The study identified 4,925 differentially methylated sites (DMSs) and prioritized the top 200 DMSs for downstream analyses. Functional enrichment analysis revealed that site-specific hypermethylation in exon 1 and distal promoter regions are linked to critical developmental processes, including morphogenesis, pattern specification, stem cell differentiation, and synaptic transmission, suggesting that these epigenetic changes may disrupt normal cellular functions and contribute to tumorigenesis. Support vector machines demonstrated the diagnostic potential of these hypermethylated sites, achieving perfect classification of LUAD and normal adjacent tissues with as few as five features. Additionally, the strong correlation between methylation levels and feature importance scores further explained the predictive accuracy of these methylation markers. The study also identified distinct methylation subgroups within LUAD tumors, independent of traditional staging, each associated with unique transcriptional dysregulation and biological processes, such as DNA repair, immune response, and ribosome biogenesis. These findings not only enhance our understanding of LUAD pathophysiology but also underscore the clinical utility of DNA methylation as a diagnostic tool and guide for patient management.