© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 7, 569-573,
April 5, 2000
© 2000 Oxford University Press
REPORTS |
E-Cadherin Gene Promoter Hypermethylation in Primary Human Gastric Carcinomas
Affiliations of authors: G. Tamura, Department of Medicine, Gastroenterology Division, University of Maryland School of Medicine, Baltimore Veterans Affairs Hospital, and Department of Pathology, Yamagata University School of Medicine, Japan; J. Yin, S. Wang, A. S. Fleisher, T. Zou, J. M. Abraham, D. Kong, K. T. Wilson, S. P. James (Department of Medicine, Gastroenterology Division), K. N. Smolinski (Department of Medicine, Gastroenterology Division, and Molecular Biology Graduate Program), S. G. Silverberg (Department of Anatomic Pathology), S. J. Meltzer (Department of Medicine, Gastroenterology Division, Greenebaum Cancer Center, and Molecular Biology Graduate Program), University of Maryland School of Medicine and Baltimore Veterans Affairs Hospital; S. Nishizuka, Department of Microbiology and Molecular Genetics, University of California, Irvine; M. Terashima, Department of Surgery, Iwate Medical University, Morioka, Japan; T. Motoyama, Department of Pathology, Yamagata University School of Medicine.
Correspondence to: Stephen J. Meltzer, M.D., Department of Medicine, Gastroenterology Division, University of Maryland, 22 S. Greene St., Rm. N3W62, Baltimore, MD 21201 (e-mail: smeltzer{at}medicine.umaryland.edu).
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 cytosine–guanosine 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.
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