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与CpG岛甲基化表型相关的胃癌异常甲基化。

Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype.

作者信息

Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin S B, Issa J P

机构信息

The Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.

出版信息

Cancer Res. 1999 Nov 1;59(21):5438-42.

Abstract

Aberrant methylation of 5' CpG islands is thought to play an important role in the inactivation of tumor suppressor genes in cancer. In colorectal cancer, a group of tumors is characterized by a hypermethylator phenotype termed CpG island methylator phenotype (CIMP), which includes methylation of such genes as p16 and hMLH1. To study whether CIMP is present in gastric cancer, the methylation status of five newly cloned CpG islands was examined in 56 gastric cancers using bisulfite-PCR. Simultaneous methylation of three loci or more was observed in 23 (41%) of 56 cancers, which suggests that these tumors have the hypermethylator phenotype CIMP. There was a significant concordance between CIMP and the methylation of known genes including p16, and hMLH1; methylation of p16 was detected in 16 (70%) of 23 CIMP+ tumors, 1 (8%) of 12 CIMP intermediate tumors, and 1 (5%) of 21 CIMP- tumors (P<0.0001). Methylation of the hMLH1 gene was detected in three of five tumors that showed microsatellite instability, and all three of the cases were CIMP+. The CIMP phenotype is an early event in gastric cancer, being present in the normal tissue adjacent to cancer in 5 of 56 cases. These results suggest that CIMP may be one of the major pathways that contribute to tumorigenesis in gastric cancers.

摘要

5' 端CpG岛的异常甲基化被认为在癌症中肿瘤抑制基因的失活过程中起重要作用。在结直肠癌中,一组肿瘤具有一种称为CpG岛甲基化表型(CIMP)的高甲基化表型特征,其中包括p16和hMLH1等基因的甲基化。为了研究CIMP是否存在于胃癌中,使用亚硫酸氢盐-PCR检测了56例胃癌中5个新克隆的CpG岛的甲基化状态。在56例癌症中的23例(41%)中观察到三个或更多位点的同时甲基化,这表明这些肿瘤具有高甲基化表型CIMP。CIMP与包括p16和hMLH1在内的已知基因的甲基化之间存在显著一致性;在23例CIMP阳性肿瘤中的16例(70%)、12例CIMP中间型肿瘤中的1例(8%)以及21例CIMP阴性肿瘤中的1例(5%)检测到p16甲基化(P<0.0001)。在5例显示微卫星不稳定性的肿瘤中有3例检测到hMLH1基因甲基化,并且所有这3例均为CIMP阳性。CIMP表型是胃癌中的一个早期事件,在56例中有5例存在于癌旁正常组织中。这些结果表明CIMP可能是导致胃癌发生的主要途径之一。

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