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...

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Published iniScience Vol. 27; no. 4; p. 109414
Main Authors Wang, Sarah S., Hall, Madison L., Lee, EunJung, Kim, Soon-Chan, Ramesh, Neha, Lee, Sang Hyub, Jang, Jin-Young, Bold, Richard J., Ku, Ja-Lok, Hwang, Chang-Il
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 19.04.2024
Elsevier
Subjects
cancer
cancer systems biology
Epigenetics
genomics
Epigenetics
genomics
cancer
cancer systems biology
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Summary: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 molecular subtype-specific DNA methylation signatures. With this approach, we identified thousands of differentially methylated regions (DMRs) that can distinguish between the stages and molecular 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 foregut endoderm 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. [Display omitted] •PDAC WGBS shows distinct methylation in stages and molecular subtypes•Late-stage PDAC has major DNA methylome shifts•Squamous PDAC subtype shows hypermethylation of GATA6 transcriptional network Genomics; Epigenetics; Cancer systems biology; Cancer
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.109414