High-density methylation of p14ARF and p16INK4A in Epstein-Barr virus-associated gastric carcinoma
High-density methylation of p14ARF and p16INK4A in Epstein-Barr virus-associated gastric carcinoma
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DOI：
10.1002/ijc.20420
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发表时间：
2004-11-01
影响因子：
6.4
通讯作者：
Fukayama, M
中科院分区：
文献类型：
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作者：
Sakuma, K;Chong, JM;Fukayama, M
EB病毒（EBV）相关胃癌（GC）中多种肿瘤相关基因的启动子高甲基化是非常常见的。为了研究启动子甲基化在这类胃癌中的意义，我们检测了EBV相关（n = 7）和EBV阴性（n = 14）胃癌中p14（ARF）和p16（INK 4A）启动子区域的甲基化密度。亚硫酸氢盐测序显示EBVaGC中p14（ARF）和p16（INK 4A）启动子区域的高频率同时甲基化。在p14（ARF）的所有29个CpG位点和p16（INK 4A）的所有16个位点中均观察到甲基化，且密度相同。在EBV阴性的GC中，2个基因的甲基化谱不同。启动子甲基化在p14（ARF）中是偶发的和可变的，并且只有p14（ARF）中的CpG的最后位置以高频率甲基化。p16（INK 4A）高密度甲基化在部分胃癌中可见，但在EBV阴性胃癌中CpG第一位从未发生甲基化。这些发现表明存在特异于EBVaGC的从头甲基化和维持甲基化机制，其可能与EBV感染相关。(C)2004 Wiley-Liss，Inc.
Promoter hypermethylation of various tumor-related genes is extremely frequent in gastric carcinoma (GC) associated with Epstein-Barr virus (EBV). To investigate the significance of the promoter methylation in this type of GC, we examined the methylation densities of the promoter regions of p14(ARF) and p16(INK4A) in EBV-associated (n = 7) and EBV-negative (n = 14) GC. Bisulfite sequencing demonstrated a high frequency of concurrent methylation of p14(ARF) and p16(INK4A) promoter regions in EBVaGC. Methylation was observed in all 29 CpG sites of p14(ARF) and all 16 sites of p16(INK4A) with equally high densities. In EBV-negative GC, the methylation profiles differed between the 2 genes. Promoter methylation was sporadic and variable in p14(ARF), and only the last position of CpG in p14(ARF) was methylated at high frequency. High-density methylation in p16(INK4A) was observed in a subset of GC, but the first position of CpG was never methylated in EBV-negative GC. These findings suggest the presence of mechanisms of de novo and maintenance methylation specific to EBVaGC that might be associated with EBV infection. (C) 2004 Wiley-Liss, Inc.