Detection of hypermethylation of the p16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus
Detection of hypermethylation of the p16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus
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作者：
Kaneto, H;Sasaki, S;Imai, K
背景/目的：p16(Ink4a)(P16)抑癌基因因启动子区域高甲基化而失活，不仅在许多类型的肿瘤中被证实，包括肝细胞癌，而且在肺、结肠、食道和胰腺的早期癌前病变中也被证实。采用甲基化特异性聚合酶链式反应(MSP)对22例肝细胞癌、17例肝硬变、17例慢性肝炎、9例原发性胆汁性肝炎(PBC)、8例自身免疫性肝炎、7例药物性肝病、6例脂肪肝和3例正常肝组织中p16基因启动子甲基化状态进行检测。结果：p16基因启动子甲基化在肝细胞癌(72.7%，16/22)、肝硬变(29.4%，5/17)和慢性肝炎(23.5%，4/17)中均为阳性。在其他任何样本中都没有检测到甲基化。所有甲基化阳性的肝细胞癌、肝硬变和慢性肝炎样本均显示p16表达缺失，并且甲基化与表达缺失之间存在显著的相关性。对甲基化阳性肝细胞癌患者系列样本的分析显示，在20例慢性肝炎患者中，18例发生了p16基因启动子甲基化的缺失。结论：我们的结果提示p16基因启动子甲基化和由此导致的p16蛋白表达缺失是肝癌发生的早期事件，它们的检测有助于肝癌高危患者的随访，如乙型或丙型肝炎病毒感染患者。
Background/aim-Inactivation of the p16(INK4A) (p16) tumour suppressor gene by promoter region hypermethylation has been demonstrated not only in many types of tumours, including hepatocellular carcinoma (HCC), but also in early preneoplastic lesions in the lung, colon, oesophagus, and pancreas. The aim of this study was to examine the methylation status of the p16 promoter in pre- and/or non-neoplastic liver diseases.Patients/subjects/methods-The methylation status of p16 was evaluated in 22 HCC, 17 cirrhosis, 17 chronic hepatitis, nine primary biliary cirrhosis (PBC), eight autoimmune hepatitis, seven drug induced liver disease, six fatty liver, and three normal Liver tissues using methylation specific polymerase chain reaction (MSP). p16 protein expression was also examined by immunohistochemical staining.Results-Methylation of the p16 promoter was detected in HCC (72.7%, 16/22) and also in cirrhosis (29.4%, 5/17) and chronic hepatitis (23.5%, 4/17), all of which were positive for hepatitis B or C virus infections. Methylation was not detected in any of the other samples. All methylation positive HCC, cirrhosis, and chronic hepatitis samples showed loss of p16 expression, and a significant correlation was found between methylation and loss of expression. Analysis of serial samples from individual patients with methylation positive HCC revealed that loss of p16 expression with promoter methylation occurred in 18 of 20 patients at the stage of chronic hepatitis without clinically detectable carcinoma.Conclusions-Our results suggest that methylation of the p16 promoter and the resulting loss of p16 protein expression are early events in a subset of hepatocarcinogenesis and that their detection is useful in the follow up of patients with a high risk of developing HCC, such as those with hepatitis B or C viral infections.