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

Clinical Cancer Research - Tập 10 Số 8 - Trang 2784-2789 - 2004
Francesco Graziano1, Federica Arduini2, Annamaria Ruzzo3, Italo Bearzi2, Bostjan Humar4, Helen More4, Rosarita Silva5, P Muretto6, Parry Guilford4, E. Testa1, Davide Mari5, Mauro Magnani3, Stefano Cascinu7
11Medical Oncology Unit, Hospital of Urbino, Urbino, Italy;
22Department of Histopathology and
34Institute of Biochemistry “G Fornaini,” University of Urbino, Urbino, Italy;
45Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand;
56Medical Oncology Unit, Hospital of Fabriano, Fabriano, Italy; and
67Department of Histopathology, Hospital of Pesaro, Pesaro, Italy
73Medical Oncology, University of Ancona, Ancona, Italy;

Tóm tắt

Abstract 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.

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Clinical Cancer Research

Tập 10 Số 8

2784-2789

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