Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma.
Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma.
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DOI：
10.1002/hep.27707
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Lind GE
中科院分区：
文献类型：
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作者：
Andresen K;Boberg KM;Vedeld HM;Honne H;Jebsen P;Hektoen M;Wadsworth CA;Clausen OP;Lundin KE;Paulsen V;Foss A;Mathisen Ø;Aabakken L;Schrumpf E;Lothe RA;Lind GE
高侵袭性恶性胆管细胞癌(CCA)的早期发现仍然是一个挑战，但有可能使肿瘤通过手术切除而治愈。这项研究通过胆刷样本的DNA甲基化分析来评估用于诊断CCA的生物标记物小组。应用甲基化特异性定量聚合酶链式反应检测93例宫颈癌组织标本中CDO1、CNRIP1、DCLK1、FBN1、INA、MAL、SEPT9、SFRP1、SNCA、SPG20、TMEFF2、VIM和ZSCAN18等13个候选基因的甲基化状态。在一系列胆刷样本(15个CCA和20个非恶性原发性硬化性胆管炎对照)中进一步分析了这13个基因，并验证了四个表现最好的标志物(34个CCA和34个原发性硬化性胆管炎对照)的甲基化状态。受试者工作特征曲线分析用于评价单个生物标志物和生物标志物组合的性能。13个候选基因在组织样本中的甲基化频率为26%-82%。在CCA患者的胆刷中，表现最好的四个基因(CDO1、CNRIP1、SEPT9和VIM)的甲基化频率分别为45%-77%。在测试和验证胆刷系列中，这一四基因生物标志物小组实现了85%的灵敏度和98%的特异度，接受者操作特征曲线下的面积为0.944。结论：我们报告了一种简单、高灵敏度和高特异度的CCA生物标志物检测方法，优于标准刷检细胞学，并建议生物标志物组合结合细胞学评估，可能会改善CCA的检测，特别是在原发性硬化性胆管炎患者中。(《肝病》2015；61：1651-1659)
Early detection of the highly aggressive malignancy cholangiocarcinoma (CCA) remains a challenge but has the potential to render the tumor curable by surgical removal. This study evaluates a biomarker panel for the diagnosis of CCA by DNA methylation analyses of biliary brush samples. The methylation status of 13 candidate genes (CDO1, CNRIP1, DCLK1, FBN1, INA, MAL, SEPT9, SFRP1, SNCA, SPG20, TMEFF2, VIM, and ZSCAN18) was investigated in 93 tissue samples (39 CCAs and 54 nonmalignant controls) using quantitative methylation‐specific polymerase chain reaction. The 13 genes were further analyzed in a test series of biliary brush samples (15 CCAs and 20 nonmalignant primary sclerosing cholangitis controls), and the methylation status of the four best performing markers was validated (34 CCAs and 34 primary sclerosing cholangitis controls). Receiver operating characteristic curve analyses were used to evaluate the performance of individual biomarkers and the combination of biomarkers. The 13 candidate genes displayed a methylation frequency of 26%‐82% in tissue samples. The four best‐performing genes (CDO1, CNRIP1, SEPT9, and VIM) displayed individual methylation frequencies of 45%‐77% in biliary brushes from CCA patients. Across the test and validation biliary brush series, this four‐gene biomarker panel achieved a sensitivity of 85% and a specificity of 98%, with an area under the receiver operating characteristic curve of 0.944. Conclusion: We report a straightforward biomarker assay with high sensitivity and specificity for CCA, outperforming standard brush cytology, and suggest that the biomarker panel, potentially in combination with cytological evaluation, may improve CCA detection, particularly among primary sclerosing cholangitis patients. (Hepatology 2015;61:1651–1659)