Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Res. 2023 Jun 2;83(11):1905-1916. doi: 10.1158/0008-5472.CAN-22-4052.
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, nonneoplastic ducts, PanIN lesions, and PDAC lesions. Differentially methylated regions (DMR) 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.
Analysis of DNA methylation landscapes provides insights into the cell-of-origin of PanIN lesions, clarifies the role of PanIN lesions as metaplastic precursors to human PDAC, and suggests potential targets for chemoprevention.
胰腺导管腺癌 (PDAC) 被认为是由一系列体细胞突变的积累引起的，并且还经常与胰腺上皮内瘤变 (PanIN) 病变相关。然而，关于人类 PanIN 和 PDAC 的细胞起源类型是腺泡还是导管，仍存在争议。由于细胞类型身份是通过表观遗传维持的，因此胰腺肿瘤发生过程中的 DNA 甲基化变化可以为研究这个问题提供一个有说服力的视角。在这里，我们对 18 名接受手术切除的患者的标本进行了激光捕获显微解剖，以高纯度分离四种相关细胞类型（腺泡、非肿瘤性导管、PanIN 病变和 PDAC 病变）的全基因组亚硫酸氢盐测序用 DNA。使用两种互补的分析方法鉴定差异甲基化区域 (DMR)：bsseq 可识别任何 DMR，但特别适用于大的块状 DMR，而 informME 则可在整个基因组上描绘潜在的能量景观，特别适用于识别差异甲基化熵。全基因组甲基化图谱和块 DMR 都清楚地表明 PanIN 起源于腺泡。在基因水平上，PanIN 病变表现出中间腺泡-导管表型，类似于腺泡到导管的化生。在 97.6%的 PanIN 特异性 DMR 中，PanIN 病变的甲基化水平介于正常和 PDAC 之间，这从信息论的角度表明 PanIN 病变在表观遗传上已经准备好向 PDAC 进展。因此，表观基因组分析补充了组织病理学，以定义向 PDAC 进展的分子进展。PanIN 和 PDAC 病变之间共享的表观遗传谱系为靶向异常甲基化的进展相关基因提供了预防的机会。
对 DNA 甲基化景观的分析提供了对 PanIN 病变细胞起源的深入了解，阐明了 PanIN 病变作为人类 PDAC 化生前体的作用，并提出了化学预防的潜在靶点。
