Monoallelic methylation of the APC promoter is altered in normal gastric mucosa associated with neoplastic lesions
Monoallelic methylation of the APC promoter is altered in normal gastric mucosa associated with neoplastic lesions
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DOI：
10.1158/0008-5472.can-03-2503
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发表时间：
2004-10-01
期刊：
影响因子：
11.2
通讯作者：
Benhattar, J
中科院分区：
文献类型：
--
作者：
Clément, G;Bosman, FT;Benhattar, J
大肠腺瘤性息肉病（APC）启动子高甲基化在正常胃粘膜中经常被报道，但这种情况是否发生在每个个体中仍有待澄清。在本研究中，通过甲基化敏感单链构象分析和甲基化敏感点印迹法分析了组织学上正常的胃粘膜样品中APC启动子的甲基化。组织切片显微解剖收集上皮细胞样本。在没有任何胃病变的患者（20个样本）的所有胃粘膜样本中发现了等量的甲基化和未甲基化APC等位基因。等位基因特异性甲基化分析表明，APC启动子的甲基化为单等位基因；然而，哪个等位基因被甲基化取决于细胞类型。36例（28%）与胃或食管腺癌相邻的正常胃粘膜样本中，有10例发现甲基化增加或减少。APC位点未发现等位基因丢失。在21例（14%）与肠化生相邻的正常胃粘膜样本中，有3例也发现了甲基化状态的改变。相比之下，所有没有化生或不典型增生的慢性胃炎患者的正常粘膜样本均显示单等位基因甲基化模式。结果表明：(a)在正常胃粘膜中，APC启动子显示单等位基因甲基化，这不是由于印迹，而很可能是由于等位基因排斥；(b)被排除的等位基因在凹窝上皮细胞和腺上皮细胞之间存在差异；(c) APC甲基化模式在胃或食管腺癌患者的正常胃粘膜中经常改变；(d)这种改变也发生在邻近肠化生的正常胃黏膜。
Adenomatous polyposis coli (APC) promoter hypermethylation has been reported frequently in normal gastric mucosa, but it remained to be clarified whether this occurs in every individual. In this study, methylation of the APC promoter was analyzed in histologically normal-appearing gastric mucosa samples by methylation-sensitive single-strand conformation analysis and by a methylation-sensitive dot blot assay. Epithelial cell samples were collected by microdissection from tissue sections. Equal amounts of methylated and unmethylated APC alleles were found in all gastric mucosa samples from patients without any gastric lesions (20 samples). Allele-specific methylation analysis showed that the methylation of the APC promoter was monoallelic; however, which allele was methylated depended on the cell type. Increased or decreased methylation was found in 10 of 36 (28%) normal gastric mucosa samples adjacent to a gastric or esophageal adenocarcinoma. No allelic loss was found at the APC locus. Modification of the methylation status was also found in 3 of 21 (14%) normal-appearing gastric mucosa samples adjacent to intestinal metaplasia. In contrast, all normal mucosa samples in cases with chronic gastritis but without metaplasia or dysplasia showed a monoallelic methylation pattern. Our results indicate the following: (a) In normal gastric mucosa, the APC promoter shows monoallelic methylation, which is not due to imprinting but most likely due to allelic exclusion; (b) the excluded allele differs between foveolar and glandular epithelial cells; (c) the APC methylation pattern is frequently altered in normal-appearing gastric mucosa of gastric or esophageal adenocarcinoma patients; and (d) such alterations also occur in normal gastric mucosa adjacent to intestinal metaplasia.