胰管腺癌（PDAC）被认为是由一系列体细胞突变积累而成，同时也经常与胰腺上皮内肿瘤（PanIN）病变相关。然而，就人类中PanIN和PDAC的细胞起源是否是腺泡或导管而言，仍有争议。由于细胞类型身份是通过表观遗传方式维持的，胰腺肿瘤期间的DNA甲基化变化可以提供一个有力的视角来研究这个问题。在这里，我们对来自18位患者的手术切除标本进行激光手术取样，以高纯度分离4种相关细胞类型的DNA全基因组双亚硫酸盐测序：泡腺、非肿瘤导管、PanIN病变和PDAC病变。使用两种互补的分析方法（bsseq和informME）鉴定了差异甲基化区域（DMRs）。bsseq可以鉴定任何DMRs，但特别适用于大块状DMRs；informME可以分析基因组中的潜在能量景观，特别适用于识别差异甲基化熵。全局甲基化剖面和块DMRs明确表明，泡腺是PanIN的起源。在基因水平上，PanIN病变展示了中间的泡腺-导管表型，类似于泡腺细胞向导管细胞化生。在97.6％的PanIN特异性DMRs中，PanIN病变的甲基化水平介于正常和PDAC之间，从信息论角度看，这表明PanIN病变在表观遗传学上是预先定位向PDAC转化。因此，表观基因组学分析与组织病理学相辅相成，定义了PDAC的分子进程。PanIN和PDAC病变之间的共享表观遗传谱系可能为通过靶向异常甲基化的进展相关基因进行预防提供了机会。

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