title: A novel CDH1 germline missense mutation in a sporadic gastric cancer patient in north-east of Italy.
abstract: It is well documented that germline mutations in the E-cadherin (CDH1) gene are linked to hereditary diffuse gastric cancer (HDGC). Despite the known molecular genetic causes, most gastric cancers are sporadic and poorly investigated for susceptibility genes. We report the finding of a novel germline missense mutation in exon 6, c. 820 G > A (p.G274S) in one sporadic gastric cancer patient. This new variant does not affect cryptic splicing of CDH1 as demonstrated by molecular assay. Immunohistochemical analysis shows a mixed pattern of E-cadherin staining (membranous and cytoplasmic) in the intestinal component, while in the diffuse counterpart, the membranous staining was prevalent and a reduced membranous expression of ß-catenin was observed. In vitro assays suggest that the mutant G274S does not affect the E-cadherin protein function, its expression pattern or subcellular localization. This new variant is present in EC2 extracellular domain of the protein (p.G120S in mature protein). The molecular modelling shows that this point mutation is not dramatic for local structure. However, p.S120 is located on the surface of the protein close to the functional calcium sites and in the region of interaction with EC1 domain of another E-cadherin molecule involved in the formation of the intercellular junction. Moreover, p.S120 residue could be involved in posttranslational modifications, such as phosphorylation or glycosylation, with possible effects on stability and integrity of adhesive properties of E-cadherin. In conclusion, the pathogenicity of this mutation is unlikely; probably we found a new germline CDH1 missense mutation with potential impact, however, of uncertain significance.
authors.affiliation: Experimental and Clinical Pharmacology Unit, Department of Molecular Oncology and Translational Medicine, DOMERT, IRCCS, National Cancer Institute, Centro di Riferimento Oncologico, Via F. Gallini, 2, 33081, Aviano, PN, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Garziera
authors.forename: Valli
authors.initials: V
authors.lastname: De Re
authors.forename: Silvano
authors.initials: S
authors.lastname: Geremia
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiredo
authors.forename: Soraia
authors.initials: S
authors.lastname: Melo
authors.forename: Joana
authors.initials: J
authors.lastname: Simões-Correia
authors.forename: Laura
authors.initials: L
authors.lastname: Caggiari
authors.forename: Mariangela
authors.initials: M
authors.lastname: De Zorzi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.forename: Renato
authors.initials: R
authors.lastname: Cannizzaro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D015703:Antigens, CD; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D005091:Exons; D005753:Gastric Mucosa / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007365:Intercellular Junctions; D007558:Italy; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin