Whole genome bisulfite sequencing identifies stage- and subtype-specific DNA methylation signatures in pancreatic cancer

In pancreatic ductal adenocarcinoma (PDAC), no recurrent metastasis-specific mutation has been found, suggesting that epigenetic mechanisms, such as DNA methylation, are the major contributors of late-stage disease progression. Here, we performed the first whole genome bisulfite sequencing (WGBS) on mouse and human PDAC organoid models to identify stage-specific and subtype-specific DNA methylation signatures in PDAC. With this approach, we identified thousands of DMRs that can distinguish between the stages and subtypes of PDAC. Stage-specific DMRs are associated with genes related to nervous system development and cell-cell adhesions and are enriched in promoters and bivalent enhancers. Subtype-specific DMRs showed hypermethylation of GATA6 transcriptional networks in the squamous subtype and hypermethylation of EMT transcriptional networks in the progenitor subtype. These results indicate that aberrant DNA methylation contributes to both PDAC progression and subtype differentiation, resulting in significant and reoccurring DNA methylation patterns with diagnostic and prognostic potential.