To Ka-Fai, Leung Wai K, Lee Tin-Lap, Yu Jun, Tong Joanna H M, Chan Michael W Y, Ng Enders K W, Chung S C Sydney, Sung Joseph J Y
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Int J Cancer. 2002 Dec 20;102(6):623-8. doi: 10.1002/ijc.10783.
Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modified DNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis.
启动子高甲基化是包括胃癌在内的人类癌症中基因沉默的一种替代机制。虽然肠化生（IM）通常被认为是胃的癌前病变，但我们的研究检测了患有和未患有胃癌的患者IM中基因启动子高甲基化的情况。我们检测了31份胃癌样本、36份胃IM样本（21份与胃癌相关，15份来自非癌症患者）以及10份正常胃活检样本。从石蜡包埋切片中仔细显微切割出含有IM病灶的组织。通过甲基化特异性PCR检测亚硫酸氢盐修饰的DNA中DAP激酶、E-钙黏蛋白、GSTP1、p14、p15、p16、RASSF1A和hMLH1基因启动子的高甲基化情况。对照胃组织均未检测到高甲基化，但在胃癌和IM中经常检测到基因启动子高甲基化。癌症和IM中甲基化基因的平均数量分别为3.0和1.4（p<0.0001）。癌症患者IM中的甲基化均与相应肿瘤样本中的同时甲基化相关。从癌症患者和非癌症患者获得的IM中甲基化基因的数量相似。通过检查这些基因的甲基化模式，识别出3种不同的甲基化模式：癌症中高甲基化比IM中更频繁（DAP激酶、p14、p15和p16）；癌症和IM中甲基化频率相当（E-钙黏蛋白和hMLH1）；以及无甲基化（GSTP1）。在癌症和非癌症患者的胃IM中经常检测到肿瘤相关基因的异常甲基化，表明它们早期参与了胃癌发生的多步骤进程。
