title: Loss of heterozygosity and promoter methylation, but not mutation, may underlie loss of TFF1 in gastric carcinoma.
abstract: It has been advanced that the trefoil factor (TFF) 1 gene is a candidate tumor-suppressor gene and may be involved in the development and/or progression of human gastric cancer. We aimed to clarify the putative role of TFF1 in gastric carcinogenesis. Ninety gastric carcinomas and eight gastric carcinoma-derived cell lines were screened for TFF1 mutations; subsets of the primary tumors and of the cell lines were subjected to loss of heterozygosity (LOH), immunohistochemistry, and promoter methylation analyses. TFF1 mutations were not detected in any of 90 gastric carcinomas. Eight (28%) of 28 informative cases displayed LOH at the TFF1 locus and absence of TFF1 staining by immunohistochemistry. These results indicate a frequent loss of TFF1 expression in gastric carcinomas through a mutation-independent mechanism. Extensive TFF1 promoter methylation was observed in nonexpressing gastric carcinoma-derived cell lines and tissues. Expressing cell lines, as well as normal gastric mucosa, presented little or no methylation of the promoter. Gastric carcinoma DNA presented de novo methylation of the promoter. These results point to the involvement of promoter methylation in the shutting down of TFF1. We conclude that TFF1 point mutations seem to be a rare event in gastric carcinogenesis. The loss of expression of TFF1 in a proportion of gastric carcinomas may be explained by LOH and methylation of the TFF1 promoter region. Our results further support the role of TFF1 inactivation in gastric carcinogenesis, in agreement with the results obtained in the Tff1-knockout mice model.
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Ralph
authors.initials: R
authors.lastname: Carvalho
authors.forename: Tuncay
authors.initials: T
authors.lastname: Kayademir
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
authors.forename: Paulo
authors.initials: P
authors.lastname: Canedo
authors.forename: Sónia
authors.initials: S
authors.lastname: Sousa
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Peter
authors.initials: P
authors.lastname: Leistenschneider
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Peter
authors.initials: P
authors.lastname: Gött
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Blin
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Machado
mesh_terms: D019175:DNA Methylation; D017353:Gene Deletion; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D010455:Peptides / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D011506:Proteins; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D006133:Growth Substances; D010455:Peptides; D011506:Proteins; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins