Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radiumhospital, Oslo, Norway.
Epigenetics. 2012 Nov;7(11):1249-57. doi: 10.4161/epi.22191. Epub 2012 Sep 14.
Cholangiocarcinoma is notoriously difficult to diagnose, and the mortality rate is high due to late clinical presentation. CpG island promoter methylation is frequently seen in cancer development. In the present study, we aimed at identifying novel epigenetic biomarkers with the potential to improve the diagnostic accuracy of cholangiocarcinoma. Microarray data analyses of cholangiocarcinoma cell lines treated with epigenetic drugs and their untreated counterparts were compared with previously published gene expression profiles of primary tumors and with non-malignant controls. Genes responding to the epigenetic treatment that were simultaneously downregulated in primary cholangiocarcinoma compared with controls (n = 43) were investigated for their promoter methylation status in cancer cell lines from the gastrointestinal tract. Genes commonly methylated in cholangiocarcinoma cell lines were subjected to quantitative methylation-specific polymerase chain reaction in a total of 93 clinical samples (cholangiocarcinomas and non-malignant controls). CDO1, DCLK1, SFRP1 and ZSCAN18, displayed high methylation frequencies in primary tumors and were unmethylated in controls. At least one of these four biomarkers was positive in 87% of the tumor samples, with a specificity of 100%. In conclusion, the novel methylation-based biomarker panel showed high sensitivity and specificity for cholangiocarcinoma. The potential of these markers in early diagnosis of this cancer type should be further explored.
胆管癌的诊断极具挑战性，由于临床症状出现较晚，死亡率较高。CpG 岛启动子甲基化在癌症的发生发展中经常出现。在本研究中，我们旨在寻找具有改善胆管癌诊断准确性潜力的新型表观遗传生物标志物。比较了经表观遗传药物处理和未经处理的胆管癌细胞系的微阵列数据分析与先前发表的原发性肿瘤的基因表达谱和非恶性对照。针对与对照相比（n=43）原发性胆管癌中同时下调的对表观遗传治疗有反应的基因，研究了其在胃肠道癌细胞系中的启动子甲基化状态。在总共 93 个临床样本（胆管癌和非恶性对照）中，对共同甲基化的基因进行了定量甲基化特异性聚合酶链反应。CDO1、DCLK1、SFRP1 和 ZSCAN18 在原发性肿瘤中显示出高甲基化频率，在对照中则未甲基化。这四个生物标志物中的至少一个在 87%的肿瘤样本中呈阳性，特异性为 100%。总之，新型基于甲基化的生物标志物组合对胆管癌具有较高的敏感性和特异性。这些标志物在该癌症类型的早期诊断中的潜力应进一步探索。
