Epigenetic regulation of cancer drivers and EMT revealed by genome-wide methylome profiling in NSCLC

Carcinogenesis is driven by dynamic and heterogeneous epigenomic alterations promoting tumour evolution and affecting therapeutic resistance. We performed genome-wide DNA methylation sequencing (RRBS) on 260 lung methylomes from 130 non-small cell lung cancer (NSCLC) patients. Here we show that gene-body hypomethylation involved lung cancer drivers, while promoter hypomethylation targeted miRNA genes linked to EGFR signalling, EMT, and PD-L1 regulation. Upstream transcription factor analysis also implicated epigenetic control of EMT, EGFR and immune pathways, through SNAIL, SLUG, SMAD3 and BRD4 . Promoter hypermethylation represented multi-gene epi-oncodriver mechanism associated with GPCRs. Subtype-specific patterns were additionally observed: adenocarcinoma showed alterations in neurotransmitter signalling, whereas squamous cell carcinoma embraced canonical oncogenic pathways. We provide a genome-wide methylome analysis in NSCLC, revealing epigenetic alterations that may contribute to tumour progression and therapeutic resistance linked to EGFR , EMT and immunological responses. These findings highlight the translational potential of epigenetic profiling to inform clinical strategies in NSCLC.