Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands.
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.
Suriano
Gianpaolo
G
Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200 Porto, Portugal.
Oliveira
Carla
C
Ferreira
Paulo
P
Machado
José C
JC
Bordin
Maria C
MC
De Wever
Olivier
O
Bruyneel
Erik A
EA
Moguilevsky
Nicole
N
Grehan
Nicola
N
Porter
Timothy R
TR
Richards
Frances M
FM
Hruban
Ralph H
RH
Roviello
Franco
F
Huntsman
David
D
Mareel
Marc
M
Carneiro
Fátima
F
Caldas
Carlos
C
Seruca
Raquel
R
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
D015820:Cadherins; D002237:Carbohydrate Dehydrogenases; C019859:cellobiose-quinone oxidoreductase