DNA methylation-mediated extracellular matrix gene silencing in colorectal cancer

Epigenetic alterations, particularly DNA methylation, play a crucial role in colorectal cancer (CRC) development and progression. We aimed to investigate DNA methylation changes across normal colon samples, adenomas, and adenocarcinomas to identify critical gene networks associated with disease progression. We conducted a comprehensive DNA methylation analysis on 2,346 samples. We extracted CRC methylation data of normal colon mucosa, adenomas, and adenocarcinomas from the genomic data commons data portal and the gene expression omnibus. We ranked differentially methylated genes by their area under the ROC curve (AUC) and retained those with AUC ≥ 0.91. Pathway enrichment analyses determined significantly impacted biological pathways, and independent gene expression datasets were employed to validate the correlation between methylation and gene expression. Our analysis identified robust hypermethylation events, particularly affecting genes involved in extracellular matrix (ECM) organization (P = 2.9E-6, adjusted P = .0017). Prominent methylation changes were mainly observed in promoter regions and first exons of key genes, including ITGA4, FBN1, COL4A1, and COL4A2, with inverse correlations between methylation and gene expression levels. Hierarchical clustering based on CpG island methylation effectively distinguished normal, adenoma, and adenocarcinoma tissues. Across this combined cohort, hypermethylation of ECM-organization genes emerged as a dominant and recurrent epigenetic program along the normal-adenoma-carcinoma sequence. These methylation patterns delineated a characteristic ECM-focused signature that was most pronounced in CRC compared with other malignancies. However, elements of this pattern were also detectable in additional tumor types. As the ECM is pivotal in regulating tumor invasion, immune evasion, and drug resistance, we propose that hypermethylation-associated disruption of ECM function may contribute to CRC progression. Our findings highlight potential biomarkers for early detection and novel therapeutic targets for epigenetic intervention.