Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer:: implications for treatment with demethylating drugs
Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer:: implications for treatment with demethylating drugs
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DOI：
10.1093/annonc/mdh108
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发表时间：
2004-03-01
影响因子：
50.5
通讯作者：
Cascinu, S
中科院分区：
文献类型：
--
作者：
Graziano, F;Arduini, F;Cascinu, S
背景：高甲基化被认为是沉默肿瘤抑制基因的一种新的相关机制。它是一种潜在的可逆表遗传改变，是具有脱甲基化活性的新型抗癌化合物的靶标。从这一角度出发，我们研究了E-钙粘蛋白基因(CDH1)启动子甲基化及其与E-钙粘蛋白蛋白表达的关系。方法：连续病例中均有可评估的石蜡包埋肿瘤块和配对的正常胃粘膜。结果：70例胃癌中有20例存在CDH1启动子甲基化，表观遗传学改变发生在早期和局部进展期。在5例正常粘膜中也检测到高甲基化。20例高甲基化肿瘤中18例为弥漫组织型(P=0.0001)。在24例E-钙粘素表达降低或阴性的肿瘤中，19例发生高甲基化，5例未发生甲基化(P=0.0001)。结论：CDH1启动子甲基化在弥漫型胃癌中常见，且与E-钙粘附素表达下调密切相关。对肿瘤抑制基因高甲基化状态的了解可能与实体瘤去甲基化药物和新的化学预防策略的开发有关。
Background: Hypermethylation is studied as a new, relevant mechanism for silencing tumor suppressor genes. It is a potentially reversible epigenetic change and it is the target of novel anticancer compounds with demethylating activity. In this perspective, we investigated E-cadherin gene (CDHl) promoter hypermethylation in gastric carcinomas and its correlation with E-cadherin protein expression.Methods: Consecutive cases of gastric carcinoma with assessable paraffin-embedded tumor blocks and paired normal mucosa were considered eligible for study entry. CDHl promoter hypermethylation and E-cadherin protein expression were determined by methylation-specific polymerase chain reaction and immunohistochemistry, respectively.Results: CDHl promoter hypermethylation was found in 20 out of 70 gastric carcinomas and the epigenetic change occurred in the early, as well as in the locally advanced disease. In five cases, hypermethylation was also detected in the normal mucosa. Eighteen out of 20 hypermethylated tumors were of the diffuse histotype (P = 0.0001). Of 24 tumors with reduced or negative E-cadherin expression, 19 were hypermethylated and 5 were unmethylated (P = 0.0001).Conclusions: CDHl promoter hypermethylation frequently occurs in gastric carcinomas of the diffuse histotype and it is significantly associated with downregulated E-cadherin expression. The knowledge on the hypermethylation status of tumor suppressor genes may be relevant to the development of demethylating drugs and novel chemopreventive strategies in solid tumors.