Kusano Masanobu, Toyota Minoru, Suzuki Hiromu, Akino Kimishige, Aoki Fumio, Fujita Masahiro, Hosokawa Masao, Shinomura Yasuhisa, Imai Kohzoh, Tokino Takashi
First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Japan.
Cancer. 2006 Apr 1;106(7):1467-79. doi: 10.1002/cncr.21789.
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.
Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined bisulfite-restriction analysis. Epstein-Barr virus (EBV)-associated gastric tumors were detected using real-time polymerase chain reaction analysis followed by an 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).
The methylation profiles of 12 genes showed nonrandom 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.
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.
CpG岛甲基化表型（CIMP）以多个基因的CpG岛同时甲基化为特征，已被公认为是胃肠道癌变的重要机制之一。
采用联合亚硫酸氢盐限制性分析检测78例原发性胃癌中5个肿瘤甲基化位点（MINT）和12个肿瘤相关基因的甲基化情况。采用实时聚合酶链反应分析检测爱泼斯坦-巴尔病毒（EBV）相关的胃肿瘤，随后评估CIMP状态、EBV相关性以及p53和K-ras基因改变之间的相关性。作者比较了高CIMP甲基化（CIMP-H）胃癌与低CIMP甲基化（CIMP-L）或阴性CIMP甲基化（CIMP-N）胃癌的临床病理特征。
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为因变量的多因素逻辑回归模型中，近端位置（P = 0.011）、弥漫型（P = 0.019）和较低的病理TNM分期（P = 0.043）对CIMP-H有显著影响。CIMP-N胃癌患者的生存率明显低于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以及无p53或K-ras突变密切相关。
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。胃癌通过不同分子途径发生这一发现可能不仅影响肿瘤特征，还影响患者预后。
