title: Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands.
abstract: E-cadherin is involved in the formation of cell-junctions and the maintenance of epithelial integrity. Direct evidence of E-cadherin mutations triggering tumorigenesis has come from the finding of inactivating germline mutations of the gene (CDH1) in hereditary diffuse gastric cancer (HDGC). We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified. We then analysed the functional significance of the two exonic missense variants found here as well as a third germline missense variant that we previously identified in a HGDC family. cDNAs encoding either the wild-type protein or mutant forms of E-cadherin were stably transfected into CHO (Chinese hamster ovary) E-cadherin-negative cells. Transfected cell-lines were characterized in terms of aggregation, motility and invasion. We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene. We also demonstrate that a proportion of missense variants are associated with significant functional consequences, suggesting that our cell model can be used as an adjunct in deciding on the potential pathogenic role of identified E-cadherin germline alterations.
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200 Porto, Portugal.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Suriano
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Paulo
authors.initials: P
authors.lastname: Ferreira
authors.forename: José C
authors.initials: JC
authors.lastname: Machado
authors.forename: Maria C
authors.initials: MC
authors.lastname: Bordin
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.forename: Erik A
authors.initials: EA
authors.lastname: Bruyneel
authors.forename: Nicole
authors.initials: N
authors.lastname: Moguilevsky
authors.forename: Nicola
authors.initials: N
authors.lastname: Grehan
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Porter
authors.forename: Frances M
authors.initials: FM
authors.lastname: Richards
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Franco
authors.initials: F
authors.lastname: Roviello
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Marc
authors.initials: M
authors.lastname: Mareel
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism*; D002237:Carbohydrate Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D006224:Cricetinae; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins; D002237:Carbohydrate Dehydrogenases; C019859:cellobiose-quinone oxidoreductase