Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer
Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer
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DOI：
10.1158/1078-0432.ccr-03-0320
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发表时间：
2004-04-15
影响因子：
11.5
通讯作者：
Cascinu, S
中科院分区：
文献类型：
--
作者：
Graziano, F;Arduini, F;Cascinu, S
目的：最近的研究表明，高甲基化是肿瘤抑制基因沉默的常见机制。这是一种潜在可逆的表观遗传变化，它是一类具有去甲基化活性的新型抗癌化合物的靶标。更好地了解高甲基化的临床意义将使未来去甲基化药物试验的最佳规划成为可能。从这个角度来看，我们研究了CDH1启动子区域的高甲基化是否与手术切除的淋巴结阳性弥漫性胃癌患者预后不良相关。实验设计：连续的弥漫性胃癌病例被认为符合入组条件。其他纳入标准包括根治性手术，至少D1淋巴结切除术，完整的随访信息，以及用于甲基化特异性PCR和免疫组织化学分析的肿瘤标本的可用性。结果：73例患者中有40例（54%）出现CDH1启动子超甲基化，且与较差的预后显著相关。在有和没有高甲基化的患者中，5年无事件生存率分别为30%和62%，5年总生存率分别为35%和67%。在多变量分析中，CDH1启动子超甲基化在无病生存（P < 0.001）和总生存（P < 0.001）中保留了其预后作用。免疫组化显示CDH1甲基化与E-cadherin表达有显著相关性（P < 0.001）。结论：本研究显示CDH1启动子高甲基化对弥漫性胃癌患者的预后有不良影响。这种形式的癌症，以及其他类型的频繁高甲基化和关键肿瘤抑制基因沉默，将成为测试具有去甲基化活性的新型化合物的合适靶点。
Purpose: Recent investigations have demonstrated that hypermethylation is a frequent mechanism for silencing tumor suppressor genes. This is a potentially reversible epigenetic change, and it is the target of a novel class of anticancer compounds with demethylating activity. Better understanding of the clinical implications of hypermethylation will allow the optimal planning of future trials with demethylating drugs. In this perspective, we investigated whether hypermethylation in the CDH1 promoter region is correlated with poor prognosis of patients with surgically resected, node-positive, diffuse gastric cancer. Experimental Design: Consecutive cases of diffuse gastric cancer were considered eligible for study entry. Additional inclusion criteria were radical surgery with a minimum of D1 lymphadenectomy, complete follow-up information, and availability of tumor specimens for methylation-specific PCR and immunohistochemistry analyses.Results: CDH1 promoter hypermethylation was found in 40 of 73 cases (54%), and it was significantly associated with worse prognosis. In patients with and without hypermethylation, the 5-year event-free survival rate was 30% and 62%, respectively, and the 5-year overall survival rate was 35% and 67%, respectively. CDH1 promoter hypermethylation retained its prognostic role for disease-free survival (P < 0.001) and overall survival (P < 0.001) in multivariate analysis. Immunohistochemistry showed a significant association between CDH1 methylation and E-cadherin expression (P < 0.001).Conclusions: This study shows adverse prognostic effect of CDH1 promoter hypermethylation in patients with diffuse gastric cancer. This form of cancer, and other types with frequent hypermethylation and silencing of critical tumor suppressor genes, would make appropriate targets for the testing of novel compounds with demethylating activity.