p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma
p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma
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DOI：
10.1158/1078-0432.ccr-04-1715
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发表时间：
2004-11-15
影响因子：
11.5
通讯作者：
Makuuchi, M
中科院分区：
文献类型：
--
作者：
Li, X;Hui, AM;Makuuchi, M
目的：在肝癌发生过程中，肿瘤抑制基因p16（INK 4A）主要通过涉及启动子高甲基化的表观遗传变化而失活。p16（INK 4A）甲基化可能的临床影响和这种表观遗传学改变的潜在危险因素尚未被彻底研究。实验设计：我们研究了50例肝细胞癌和相应的非肿瘤性肝病变中p16（INK 4A）的甲基化状态和mRNA及蛋白表达，采用甲基化特异性PCR、逆转录PCR和免疫组化技术。在58%（29/50）的肝细胞癌和16%（6/38）的相应慢性肝炎和肝硬化组织样本中观察到p16（INK 4A）超甲基化。p16（INK 4A）甲基化与mRNA和蛋白表达显著相关（分别为P < 0.001和P = 0.003）。所有p16（INK 4A）甲基化肿瘤均为B型肝炎病毒或丙型肝炎病毒标志物阳性，但病毒阴性肿瘤均未显示p16（INK 4A）甲基化（P = 0.006）。丙型肝炎病毒相关肿瘤中p16（INK 4A）高甲基化的频率（23/32，72%）往往高于乙型肝炎病毒相关肿瘤（6/13，46%; P = 0.1）。B病毒相关肿瘤。p16（INK 4A）的异常甲基化也与年龄增加、女性性别和血清PIVKA-II正常水平显著相关（分别为P = 0.02、0.04和0.04）。p16（INK 4A）高甲基化患者的生存率无统计学显著差异，观察和那些没有.Conclusions：我们的观察表明，p16（INK 4A）高甲基化可能有助于从早期阶段的肝癌发生和多种危险因素，如病毒感染，年龄和性别，可能与p16（INK 4A）高甲基化在肝癌发生。
Purpose: The tumor suppressor gene p16(INK4A) is mainly inactivated by an epigenetic change involving promoter hypermethylation in hepatocarcinogenesis. The possible clinical impact of p16(INK4A) methylation and the potential risk factors for this epigenetic alteration have not been thoroughly investigated.Experimental Design: We studied the methylation status and mRNA and protein expression of p16(INK4A) in 50 hepatocellular carcinomas and corresponding nonneoplastic liver lesions using methylation-specific PCR, reverse transcription-PCR, and immunohistochemical techniques.Results: p16(INK4A) hypermethylation was observed in 58% (29 of 50) of the hepatocellular carcinomas and 16% (6 of 38) of the corresponding chronic hepatitis and cirrhosis tissue samples. p16(INK4A) methylation was significantly associated with mRNA and protein expression (P < 0.001 and P = 0.003, respectively). All of the p16(INK4A)-methylated tumors were positive for hepatitis B virus or hepatitis C virus markers, but none of the virus-negative tumors exhibited p16(INK4A) methylation (P = 0.006). The frequency of p16(INK4A) hypermethylation tended to be higher in hepatitis C virus-related tumors (23 of 32, 72%) than in hepatitis B virus-related tumors (6 of 13, 46%; P = 0.1). Aberrant methylation of p16(INK4A) was also related significantly to increasing age, female gender, and normal levels of serum PIVKA-II (P = 0.02, 0.04, and 0.04, respectively). No statistically significant difference in survival was observed between patients with p16(INK4A) hypermethylation and those without.Conclusions: Our observations suggest that p16(INK4A) hypermethylation may contribute to hepatocarcinogenesis from an early stage and that multiple risk factors, such as viral infections, age, and gender, may be associated with p16(INK4A) hypermethylation in hepatocarcinogenesis.