巴雷特食管和食管腺癌中异常DNA甲基化的相似性。
Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma.
作者信息
Smith Eric, De Young Neville J, Pavey Sandra J, Hayward Nicholas K, Nancarrow Derek J, Whiteman David C, Smithers B Mark, Ruszkiewicz Andrew R, Clouston Andrew D, Gotley David C, Devitt Peter G, Jamieson Glyn G, Drew Paul A
机构信息
School of Nursing and Midwifery, Flinders University, Bedford Park, South Australia 5042, Australia.
出版信息
Mol Cancer. 2008 Oct 2;7:75. doi: 10.1186/1476-4598-7-75.
BACKGROUND
Barrett's esophagus (BE) is the metaplastic replacement of squamous with columnar epithelium in the esophagus, as a result of reflux. It is the major risk factor for the development of esophageal adenocarcinoma (EAC). Methylation of CpG dinucleotides of normally unmethylated genes is associated with silencing of their expression, and is common in EAC. This study was designed to determine at what stage, in the progression from BE to EAC, methylation of key genes occurs.
RESULTS
We examined nine genes (APC, CDKN2A, ID4, MGMT, RBP1, RUNX3, SFRP1, TIMP3, and TMEFF2), frequently methylated in multiple cancer types, in a panel of squamous (19 biopsies from patients without BE or EAC, 16 from patients with BE, 21 from patients with EAC), BE (40 metaplastic, seven high grade dysplastic) and 37 EAC tissues. The methylation frequency, the percentage of samples that had any extent of methylation, for each of the nine genes in the EAC (95%, 59%, 76%, 57%, 70%, 73%, 95%, 74% and 83% respectively) was significantly higher than in any of the squamous groups. The methylation frequency for each of the nine genes in the metaplastic BE (95%, 28%, 78%, 48%, 58%, 48%, 93%, 88% and 75% respectively) was significantly higher than in the squamous samples except for CDKN2A and RBP1. The methylation frequency did not differ between BE and EAC samples, except for CDKN2A and RUNX3 which were significantly higher in EAC. The methylation extent was an estimate of both the number of methylated alleles and the density of methylation on these alleles. This was significantly greater in EAC than in metaplastic BE for all genes except APC, MGMT and TIMP3. There was no significant difference in methylation extent for any gene between high grade dysplastic BE and EAC.
CONCLUSION
We found significant methylation in metaplastic BE, which for seven of the nine genes studied did not differ in frequency from that found in EAC. This is also the first report of gene silencing by methylation of ID4 in BE or EAC. This study suggests that metaplastic BE is a highly abnormal tissue, more similar to cancer tissue than to normal epithelium.
背景
巴雷特食管（BE）是食管鳞状上皮被柱状上皮化生取代的结果，由反流引起。它是食管腺癌（EAC）发生的主要危险因素。正常情况下未甲基化基因的CpG二核苷酸甲基化与其表达沉默相关，且在EAC中常见。本研究旨在确定在从BE进展为EAC的哪个阶段发生关键基因的甲基化。
结果
我们检测了9个基因（APC、CDKN2A、ID4、MGMT、RBP1、RUNX3、SFRP1、TIMP3和TMEFF2），这些基因在多种癌症类型中常发生甲基化，检测对象包括一组鳞状组织（19例来自无BE或EAC的患者活检样本，16例来自BE患者，21例来自EAC患者）、BE组织（40例化生组织、7例高级别异型增生组织）以及37例EAC组织。EAC中这9个基因各自的甲基化频率，即有任何程度甲基化的样本百分比（分别为95%、59%、76%、57%、70%、73%、95%、74%和83%）显著高于任何鳞状组织组。化生型BE中这9个基因各自的甲基化频率（分别为95%、28%、78%、48%、58%、48%、93%、88%和75%）除CDKN2A和RBP1外，均显著高于鳞状样本。除CDKN2A和RUNX3在EAC中显著更高外，BE和EAC样本的甲基化频率无差异。甲基化程度是对甲基化等位基因数量及其在这些等位基因上的甲基化密度的估计。除APC、MGMT和TIMP3外，所有基因在EAC中的甲基化程度均显著高于化生型BE。高级别异型增生型BE和EAC之间任何基因的甲基化程度均无显著差异。
结论
我们发现化生型BE中存在显著甲基化，在所研究的9个基因中有7个基因的甲基化频率与EAC中的频率无差异。这也是关于ID4在BE或EAC中因甲基化导致基因沉默的首次报道。本研究表明化生型BE是一种高度异常的组织，与癌组织的相似性高于正常上皮组织。
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