Reprimo methylation is a potential biomarker of Barrett's-associated esophageal neoplastic progression
Reprimo methylation is a potential biomarker of Barrett's-associated esophageal neoplastic progression
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DOI：
10.1158/1078-0432.ccr-06-1781
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发表时间：
2006-11-15
影响因子：
11.5
通讯作者：
Meltzer, Stephen J.
中科院分区：
文献类型：
--
作者：
Hamilton, James P.;Sato, Fumiaki;Meltzer, Stephen J.
目的：候选抑癌基因Reprimo调控P53介导的细胞周期停滞于G(2)期，抑癌基因甲基化参与食管癌的发生发展。我们的目的是确定Barrett腺癌的发生是否以及在肿瘤进展的哪个阶段发生Reprimo甲基化，以及其柱状或鳞状细胞类型的特异性。我们还试图确定去甲基化试剂5-氮杂脱氧胞苷(5AzaC)能否在体外恢复Reprimo的表达。实验设计：使用AB17700(Taqman)仪对175例内窥镜活检标本进行Reprimo的甲基化特异性定量PCR。结果：在Barrett‘s食管组(BE，P=0.001)、高度不典型增生(HGD，P=0.001)和食管腺癌(EAC，P=0.00003)中，Reprimo甲基化水平和频率均显著高于正常食管组(NE)。BE与EAC、HGD与EAC、NE与食管鳞癌之间的表达差异无统计学意义。19例NE中0例发生Reprimo甲基化，45例ESCC中6例(13%)，25例BE中9例(36%)，11例HGD中7例(%)，75例EAC中47例(63%)发生Reprimo甲基化。EAC和NE的Reprimo甲基化分析显示，接受者-操作者特征曲线下的区域为0.812(P<；0.00001；95%可信区间0.73-0.9)。结论：BE、HGD和EAC中Reprimo甲基化的发生频率明显高于NE和ESCC，提示这种表观遗传改变是一种特殊的柱状、细胞特异性的早期事件，有可能成为早期发现食管瘤的生物标志物。
Purpose: Reprimo, a candidate tumor-suppressor gene, regulates p53-mediated cell cycle arrest at G(2) phase, and tumor-suppressor gene methylation is involved in the pathogenesis and progression of esophageal cancer. Our aim was to determine whether and at what phase of neoplastic progression Reprimo methylation occurs in Barrett's adenocarcinogenesis, as well as its columnar or squamous cell-type specificity. We also sought to determine whether Reprimo expression could be restored in vitro by the demethylating agent 5-aza-deoxycytidine (5AzaC).Experimental Design: Quantitative methylation-specific PCR for Reprimo was done using an AB17700 (Taqman) apparatus on 175 endoscopic biopsy specimens. In addition, reverse transcription-PCR and quantitative methylation-specific PCR were done on esophageal carcinoma cells before and after treatment with 5AzaC.Results: In Barrett's esophagus (BE; P = 0.001), high-grade dysplasia (HGD; P = 0.001), and esophageal adenocarcinoma (EAC; P = 0.00003), the level and frequency of Reprimo methylation were significantly higher than in normal esophagus (NE). There was no statistically significant difference between BE and EAC, HGD and EAC, or NE and esophageal squamous cell carcinoma (ESCC). Reprimo methylation occurred in 0 of 19 NE samples, 6 (13%) of 45 ESCC, 9 (36%) of 25 BE, 7 (64%) of 11 HGD, and 47 (63%) of 75 EAC. Analysis of Reprimo methylation in EAC versus NE revealed an area under the receiver-operator characteristic curve of 0.812 (P < 0.00001; 95% confidence interval, 0.73-0.90). In vitro 5AzaC treatment of OE33 EAC cells reduced Reprimo methylation and increased Reprimo expression.Conclusions: Reprimo methylation occurs significantly more frequently in BE, HGD, and EAC than in NE or ESCC, suggesting that this epigenetic alteration is a specialized columnar, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.