Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is believed to arise ylation entropy. Both global methylation profiles and block DMRs from the accumulation of a series of somatic mutations and is also clearly implicated an acinar origin for PanINs. At the gene level, frequently associated with pancreatic intraepithelial neoplasia PanIN lesions exhibited an intermediate acinar-ductal phenotype (PanIN) lesions. However, there is still debate as to whether the resembling acinar-to-ductal metaplasia. In 97.6% of PanIN-specific cell type-of-origin of PanINs and PDACs in humans is acinar or DMRs, PanIN lesions had an intermediate methylation level ductal. As cell type identity is maintained epigenetically, DNA between normal and PDAC, which suggests from an information methylation changes during pancreatic neoplasia can provide a theory perspective that PanIN lesions are epigenetically primed to compelling perspective to examine this question. Here, we per- progress to PDAC. Thus, epigenomic analysis complements histoformed laser-capture microdissection on surgically resected speci- pathology to define molecular progression toward PDAC. The mens from 18 patients to isolate, with high purity, DNA for whole- shared epigenetic lineage between PanIN and PDAC lesions could genome bisulfite sequencing from four relevant cell types: acini, provide an opportunity for prevention by targeting aberrantly nonneoplastic ducts, PanIN lesions, and PDAC lesions. Differen- methylated progression-related genes. tially methylated regions (DMR) were identified using two complementary analytical approaches: bsseq, which identifies any Significance: Analysis of DNA methylation landscapes provides DMRs but is particularly useful for large block-like DMRs, and insights into the cell-of-origin of PanIN lesions, clarifies the role of informME, which profiles the potential energy landscape across the PanIN lesions as metaplastic precursors to human PDAC, and genome and is particularly useful for identifying differential meth- suggests potential targets for chemoprevention.