E-cadherin gene promoter hypermethylation in primary human gastric carcinomas

Gen Tamura, Jing Yin, Suna Wang, A. S. Fleisher, Tongtong Zou, John M. Abraham, Dehe Kong, Kara N. Smolinski, Keith T. Wilson, Stephen P. James, Steven G. Silverberg, Satoshi Nishizuka, Masanori Terashima, Teiichi Motoyama, Stephen J. Meltzer

Research output: Contribution to journalArticlepeer-review

Abstract

Background: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas. Methods: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)-single-strand conformation polymorphism (MSP- SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided. Results: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP-SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P = .0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P = .73, Fisher's exact test). Methylation occurring at all cytosineguanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite-DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation. Conclusions: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.

Original languageEnglish (US)
Pages (from-to)569-573
Number of pages5
JournalJournal of the National Cancer Institute
Volume92
Issue number7
DOIs
StatePublished - Apr 5 2000
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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