G 蛋白偶联胆汁酸受体 Gpbar1（TGR5）的异常 DNA 甲基化是乙型肝炎病毒相关肝细胞癌的潜在生物标志物。
Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a potential biomarker for hepatitis B Virus associated hepatocellular carcinoma.
机构信息
1. Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China ; 2. Institute of Hepatology, Shandong University, Jinan 250012, China.
3. Department of Ultrasound, the General Hospital Jinan Military Region, Jinan 250031, China.
出版信息
Int J Med Sci. 2014 Jan 7;11(2):164-71. doi: 10.7150/ijms.6745. eCollection 2014.
BACKGROUND
G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients.
METHODS
The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP).
RESULTS
Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients ≥60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50.
CONCLUSIONS
Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients.
背景
G 蛋白偶联胆汁酸受体 Gpbar1（TGR5）是一种新发现的肝癌发生过程中的肿瘤抑制因子。本研究旨在确定血清 TGR5 启动子甲基化在鉴别慢性乙型肝炎（CHB）患者肝癌（HCC）中的潜在价值。
方法
从包括 160 例 HCC、88 例 CHB 和 45 例健康对照（HC）的回顾性数据集提取循环无细胞 DNA（cfDNA）。采用甲基化特异性聚合酶链反应（MSP）检测 TGR5 启动子的甲基化状态。
结果
HCC 中 TGR5 启动子超甲基化的发生率明显高于 CHB（12/88，13.64%；p<0.01）和 HCs（2/45，4.44%；p<0.01）。≥60 岁 HCC 患者的 TGR5 甲基化率明显高于<60 岁的患者（p<0.05）。甲胎蛋白（AFP）在截断值为 20、200 和 400ng/ml 时的灵敏度分别为 58.13%、30.63%和 24.38%；而 TGR5 甲基化联合 AFP 的灵敏度为 81.25%、68.13%和 65%。AFP 在截断值为 20、200 和 400ng/ml 时的特异性分别为 47.73%、92.05%和 98.86%；而 TGR5 甲基化联合 AFP 的特异性为 38.64%、78.41%和 85.23%。AFP 在截断值为 20、200 和 400ng/ml 时的 Youden 指数分别为 0.06、0.23 和 0.23；而 TGR5 甲基化联合 AFP 的 Youden 指数分别为 0.20、0.47 和 0.50。
结论
我们的研究结果强烈表明，血清 TGR5 启动子甲基化与 AFP 的联合检测可提高 AFP 单独鉴别 HCC 与 CHB 患者的诊断价值。
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