Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus
Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus
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DOI：
10.1002/cncr.21789
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发表时间：
2006-04-01
期刊：
影响因子：
6.2
通讯作者：
Tokino, T
中科院分区：
文献类型：
--
作者：
Kusano, M;Toyota, M;Tokino, T
背景CpG岛甲基化表型（CpG island methylator phenotype，CIMP）是多个基因CpG岛同时甲基化的特征，是胃肠道肿瘤发生的重要机制之一。应用联合限制性内切酶分析技术检测了78例原发性胃癌组织中5个肿瘤甲基化位点和12个肿瘤相关基因的甲基化状态。使用实时聚合酶链反应分析检测EB病毒（EBV）相关胃肿瘤亚硫酸氢盐，然后评估CIMP状态、EBV相关性和p53和K-ras基因改变之间的相关性。作者比较了具有高CIMP甲基化（CIMP-H）的胃癌与具有低CIMP甲基化（CIMP-L）或CIMP甲基化阴性（CIMP-N）的肿瘤的临床病理学特征。12个基因的甲基化谱显示非随机甲基化，支持胃癌中存在CIMP。在CIMP-H肿瘤中未检测到p53突变，在显示p53和K-ras突变的肿瘤中未检测到EBV相关性。在以CIMP-H为因变量的多元Logistic回归模型中，近端位置（P = 0.011）、弥漫型（P = 0.019）和不太晚期的病理TNM状态（P = 0.043）对CIMP-H有显著影响。CIMP-N胃肿瘤患者的生存率显著低于CIMP-H肿瘤患者（P = 0.004）或CIMP-L肿瘤患者（P = 0.012）。EBV相关肿瘤与CIMP-H、肿瘤相关基因的高甲基化密切相关，而无p53或K-ras突变。CIMP状态似乎与胃癌不同的遗传、表观遗传和临床病理特征相关。胃癌通过不同的分子途径发生的发现不仅可能影响肿瘤的特性，而且可能影响患者的预后。
BACKGROUND. The CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis.METHODS. Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined-restriction analysis. Epstein-Barr virus (EBV)-associated gastric tumors bisulfite were detected using real-time polymerase chain reaction analysis followed by all evaluation of the correlations between CIMP status, EBV-association, and genetic alteration of p53 and K-ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP-H) with tumors that had low CIMP methylation (CIMP-L) or negative CIMP methylation (CIMP-N).RESULTS. The methylation profiles of 12 genes showed non-random methylation, Supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP-H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K-ras. In a multiple logistic regression model with CIMP-H as the dependent variable, proximal location (P =.011), diffuse type (P =.019), and less advanced pathologic TNM status (P =.043) contributed significantly to CIMP-H. Patients who had CIMP-N gastric tumors had a significantly worse Survival than patients who had CIMP-H tumors (P =.004) or CIMP-L tumors (P =.012). EBV-associated tumors were associated strongly with CIMP-H, hypermethylation of tumor-related genes, and no p53 or K-ras mutation.CONCLUSIONS. CIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis.