Whole-genome bisulfite sequencing identifies stage- and subtype-specific DNA methylation signatures in pancreatic cancer
Sarah S. Wang,
Madison L. Hall,
EunJung Lee,
Soon-Chan Kim,
Neha Ramesh,
Sang Hyub Lee,
Jin-Young Jang,
Richard J. Bold,
Ja-Lok Ku,
Chang-Il Hwang
Affiliations
Sarah S. Wang
Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, Davis, CA 95616, USA
Madison L. Hall
Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, Davis, CA 95616, USA
EunJung Lee
Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, Davis, CA 95616, USA
Soon-Chan Kim
Department of Biomedical Sciences, Korean Cell Line Bank, Laboratory of Cell Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
Neha Ramesh
Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, Davis, CA 95616, USA
Sang Hyub Lee
Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
Jin-Young Jang
Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
Richard J. Bold
Division of Surgical Oncology, Department of Surgery, University of California, Davis, Sacramento, CA, USA; University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
Ja-Lok Ku
Department of Biomedical Sciences, Korean Cell Line Bank, Laboratory of Cell Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
Chang-Il Hwang
Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, Davis, CA 95616, USA; University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA; Corresponding author
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.
