title: Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Medical Oncology Unit, Hospital of Urbino, Urbino, Italy. frada@tin.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
authors.forename: Federica
authors.initials: F
authors.lastname: Arduini
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ruzzo
authors.forename: Italo
authors.initials: I
authors.lastname: Bearzi
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Helen
authors.initials: H
authors.lastname: More
authors.forename: Rosarita
authors.initials: R
authors.lastname: Silva
authors.forename: Pietro
authors.initials: P
authors.lastname: Muretto
authors.forename: Parry
authors.initials: P
authors.lastname: Guilford
authors.forename: Enrica
authors.initials: E
authors.lastname: Testa
authors.forename: Davide
authors.initials: D
authors.lastname: Mari
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
mesh_terms: D000328:Adult; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D018572:Disease-Free Survival; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D013997:Time Factors
chemical_list: D015820:Cadherins; D017931:DNA Primers