Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa
Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa
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DOI：
10.1136/gut.2005.089813
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发表时间：
2007-01-01
期刊：
影响因子：
24.5
通讯作者：
Matsubara, N.
中科院分区：
文献类型：
--
作者：
Ishii, T.;Murakami, J.;Matsubara, N.
背景：食管鳞状细胞癌（OSCC）通常起源于食管上皮的不典型增生病变。然而，发生在癌前病变的分子变化并没有很好地理解。表观遗传学变化是一个例子，OSCC可能发生在epithelium.Aim：探讨多个启动子的甲基化状态在癌症衍生的DNA，以及在背景上皮的OSCC，包括不典型增生病变和非肿瘤性粘膜。还检查了来自非癌症患者的正常上皮。研究对象和方法：56例晚期口腔鳞癌、21例上皮内瘤变（IEN）、56例癌旁非肿瘤上皮和42例正常对照。采用甲基化特异性单聚合酶链反应（PCR）和亚硫酸氢盐限制性内切酶分析（RFLP）检测SFRP 1、SFRP 2、DCC、APC、p16（INK 4a）、p14（ARF）、MINT 1、MINT 2、MINT 31、CACNA 1G、COX 2、DAPK、hMLH 1和MGMT基因启动子甲基化状态。结果：在口腔鳞癌组织及癌旁组织中均发现了p53基因的甲基化。CpG岛甲基化的频率从背景非肿瘤上皮的基线水平增加，通过IEN，到晚期OSCC。然而，p53突变几乎只在肠上皮内瘤样病变和口腔鳞癌中观察到。p53基因突变的肿瘤性病变（OSCC或IEN）中DNA甲基化程度高于野生型p53基因突变的肿瘤性病变。结论：DNA甲基化在非肿瘤性食管上皮中存在，并参与了OSCC癌变过程中的不典型增生-癌变序列的进展。
Background: Oesophageal squamous cell carcinoma (OSCC) often arises from preceding dysplastic lesions in the oesophageal epithelium. However, the molecular changes occurring in premalignant lesions are not well understood. An epigenetic change is an example of OSCC that may occur within the epithelium.Aim: To investigate the methylation status of multiple promoters in cancer-derived DNA, as well as in the background epithelium of OSCC, including dysplastic lesions and non-neoplastic mucosa. The normal epithelium from patients without cancer was also examined. The findings were correlated with the mutational status of p53.Patients and methods: 56 patients with advanced OSCC, 21 patients with intraepithelial neoplasia (IEN), 56 patients with a background of non-neoplastic epithelium, adjacent to the OSCC, and 42 normal control epithelia from healthy volunteers were studied. The promoter methylation status of SFRP1, SFRP2, DCC, APC, p16(INK4a), p14(ARF), MINT1, MINT2, MINT31, CACNA1G, COX2, DAPK, hMLH1 and MGMT was examined by methylation-specific single polymerase chain reaction or combined bisulphite restriction analysis. The mutation of p53 by direct sequencing was assessed.Results: DNA methylation was observed in OSCC and in its background epithelium. The frequency of CpG island methylation increased from a baseline level in the background non-neoplastic epithelium, through IEN, to advanced OSCC. However, mutations in p53 were almost exclusively observed in IEN and OSCC. More extensive DNA methylation was seen in the neoplastic lesions (OSCC or IEN) having a p53 mutation than in those with wild-type p53.Conclusion: DNA methylation is present at low levels in the non-neoplastic oesophageal epithelium and appears to contribute to the progression of the dysplasia-carcinoma sequence in OSCC carcinogenesis.