Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, South Korea.
Virchows Arch. 2019 Jul;475(1):49-58. doi: 10.1007/s00428-018-02511-7. Epub 2019 Jan 4.
Intrahepatic cholangiocarcinoma is a complex disease with three different histologic subtypes, the large duct, small duct, and bile ductular types. In the present study, we elucidated whether the three histological subtypes have differences in their methylation profiles and developed a DNA methylation marker that might help identify a subset of ICC with a different prognosis. We screened 113 promoter CpG island loci against 10 cases of intrahepatic cholangiocarcinoma and normal cystic ducts using the MethyLight assay and selected 30 CpG island loci with cancer-associated hypermethylation. Then, we analyzed 172 intrahepatic cholangiocarcinomas for the methylation state at these 30 loci. Six loci, including DLEC1, were more frequently methylated in the bile ductular type and small duct type, whereas six loci were more frequently methylated in the large duct type. Of these 30 loci, DLEC1 methylation was found mainly in the bile ductular type and small duct type but rarely in the large duct type. DLEC1 methylation was significantly associated with a better clinical outcome in intrahepatic cholangiocarcinomas of the small duct type but not of the bile ductular type. DLEC1 methylation was an independent prognostic variable in both cancer-specific survival and recurrence-free survival. For patients with intrahepatic cholangiocarcinoma of the small duct type (n = 68), DLEC1 methylation was found in 26 (38.2%) and was associated with a better clinical outcome for both cancer-specific survival and recurrence-free survival. Our findings suggest that DLEC1 methylation can be utilized to identify a subset with a better prognosis in intrahepatic cholangiocarcinomas of the small duct type.
肝内胆管癌是一种复杂的疾病，具有三种不同的组织学亚型，即大导管型、小导管型和胆管型。在本研究中，我们阐明了这三种组织学亚型在甲基化谱上是否存在差异，并开发了一种 DNA 甲基化标志物，可能有助于识别具有不同预后的 ICC 亚群。我们使用 MethyLight 检测法对 10 例肝内胆管癌和正常囊性胆管中的 113 个启动子 CpG 岛进行了筛选，并选择了 30 个与癌症相关的高甲基化 CpG 岛。然后，我们分析了 172 例肝内胆管癌中这些 30 个位点的甲基化状态。包括 DLEC1 在内的 6 个位点在胆管型和小导管型中更频繁地发生甲基化，而 6 个位点在大导管型中更频繁地发生甲基化。在这 30 个位点中，DLEC1 甲基化主要发生在胆管型和小导管型中，而很少发生在大导管型中。DLEC1 甲基化与小导管型肝内胆管癌的较好临床预后显著相关，但与胆管型肝内胆管癌无关。DLEC1 甲基化是小导管型肝内胆管癌患者癌症特异性生存和无复发生存的独立预后因素。对于小导管型肝内胆管癌患者（n=68），发现 DLEC1 甲基化 26 例（38.2%），与癌症特异性生存和无复发生存均相关。我们的研究结果表明，DLEC1 甲基化可用于识别小导管型肝内胆管癌中预后较好的亚群。
