This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Graziano, F. Articles by Cascinu, S. Search for Related Content PubMed PubMed Citation Articles by Graziano, F. Articles by Cascinu, S.

Prognostic Analysis of E-Cadherin Gene Promoter Hypermethylation in Patients with Surgically Resected, Node-Positive, Diffuse Gastric Cancer

¹ Medical Oncology Unit, Hospital of Urbino, Urbino, Italy; ² Department of Histopathology and ³ Medical Oncology, University of Ancona, Ancona, Italy; ⁴ Institute of Biochemistry "G Fornaini," University of Urbino, Urbino, Italy; ⁵ Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand; ⁶ Medical Oncology Unit, Hospital of Fabriano, Fabriano, Italy; and ⁷ Department of Histopathology, Hospital of Pesaro, Pesaro, Italy

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.

This article has been cited by other articles:

				P. Muretto, A. Ruzzo, F. Pizzagalli, F. Graziano, P. Maltese, C. Zingaretti, E. Berselli, N. Donnarumma, and M. Magnani Endogastric capsule for E-cadherin gene (CDH1) promoter hypermethylation assessment in DNA from gastric juice of diffuse gastric cancer patients Ann. Onc., March 1, 2008; 19(3): 516 - 519. [Abstract] [Full Text] [PDF]

				M. F.G. de Maat, C. J.H. van de Velde, N. Umetani, P. de Heer, H. Putter, A. Q. van Hoesel, G. A. Meijer, N. C. van Grieken, P. J.K. Kuppen, A. J. Bilchik, et al. Epigenetic Silencing of Cyclooxygenase-2 Affects Clinical Outcome in Gastric Cancer J. Clin. Oncol., November 1, 2007; 25(31): 4887 - 4894. [Abstract] [Full Text] [PDF]

				J. Gu, D. Berman, C. Lu, I. I. Wistuba, J. A. Roth, M. Frazier, M. R. Spitz, and X. Wu Aberrant Promoter Methylation Profile and Association with Survival in Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., December 15, 2006; 12(24): 7329 - 7338. [Abstract] [Full Text] [PDF]

				Y. Yuan, J. Wang, J. Li, L. Wang, M. Li, Z. Yang, C. Zhang, and J. L. Dai Frequent Epigenetic Inactivation of Spleen Tyrosine Kinase Gene in Human Hepatocellular Carcinoma. Clin. Cancer Res., November 15, 2006; 12(22): 6687 - 6695. [Abstract] [Full Text] [PDF]

				J. Proll, M. Fodermayr, C. Wechselberger, P. Pammer, M. Sonnleitner, O. Zach, and D. Lutz Ultra-Sensitive Immunodetection of 5'Methyl Cytosine for DNA Methylation Analysis on Oligonucleotide Microarrays DNA Res, January 1, 2006; 13(1): 37 - 42. [Abstract] [Full Text] [PDF]

				P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF]