Abstract 4940: E-cadherin methylation is preceded in normal mucosa of diffuse type gastric carcinoma

Abstract

Abstract Background: The importance of loss of E-cadherin (encoded by CDH1) to cancer progression is well established. CDH1 is mutationally inactivated in nearly half of diffuse type gastric cancer (DGC). Although CDH1 promoter methylation has been suggested to be a major second hit in hereditary diffuse gastric cancer, its role in sporadic DGCs is not clarified. Searching for the second hit methylation in potential precursor lesions in sporadic DGC, we investigated the CDH1 methylation frequency in a series of DGCs and matching normal mucosas and then compared the result with the CDH1 methylation frequency in normal mucosas from benign gastric pathology. Materials and Methods: The extent of promoter methylation of CDH1 gene was assessed quantitatively using Pyrosequencing in 72 DGCs with two matching normal mucosas from adjacent and remote foci, and 24 normal gastric mucosa samples from patients with benign gastric pathology. Gene product was studied by immunohistochemistry and the relationship between methylation profile of gene promoter and clinicopathological parameters was analyzed. Results: The Pyrosequencing analysis of DGCs revealed a high frequency of CDH1 methylation in 77.8% (56/72). The methylation frequency for CDH1 gene in matching normal mucosas from adjacent and remote foci was 70.8% (51/72) and 72.2% (52/72), respectively. According to the distance from the tumor location the result did not show significant difference. Moreover, total of 65 out of 72 cases (90.3%) showed at least one focus with CDH1 methylation. Frequency of CDH1 methylation in normal gastric mucosa samples with benign gastric pathology was 50.0% (12/24). There was a significant difference of CDH1 methylation in between normal mucosas from DGCs and normal mucosas with benign gastric pathology (90.3% vs. 50.0%, respectively, p<0.001). CDH1 methylation in matching normal gastric mucosas was counted as a statistically significant risk factor when adjusted for age and sex using a binary logistic regression model (p<0.001). Additionally loss or diminished expression of E-cadherin was confirmed by immunohistochemistry in 69 of 72 tumor samples (96.9%) and its down expression was not uncommonly observed in adjacent normal gastric mucosas. Conclusion: We found that CDH1 promoter methylation in the normal gastric mucosas from DGC samples was significantly higher than in the normal gastric mucosas with benign pathology but had a similar frequency with tumor tissues. These results suggest that CDH1 gene methylation may be important in the initial development of sporadic DGC tumorigenesis and the presence of DGC progenitor cells may be traced by the E-cadherin down-expression in normal gastric mucosa from different foci. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4940.