title: E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer.
abstract: To identify germline E-cadherin mutations responsible for the predisposition to diffuse gastric cancer (DGC) among the Japanese, we screened 17 patients with familial aggregation of gastric cancer by sequencing analysis. All the patients were diagnosed with DGC and had at least 1 sibling with gastric cancer. Two novel E-cadherin gene variants were detected. One was detected in 1 patient only and associated with an amino acid substitution (Val/Met) at codon 832 in the region essential for binding to beta-catenin. The M832 variant was detected not only in the proband but also in 2 other gastric cancer patients in the family. Immunohistochemical analysis of gastric cancer tissue from the proband revealed that E-cadherin expression was markedly reduced and beta-catenin expression was also reduced in cancer cells. However, no significant difference in the activity of beta-catenin binding was detected between the M832 variant and V832 wild-type E-cadherin in immunofluorescence and immunoprecipitation/Western blot analyses. The other was detected in 5 patients and was located in the splice donor site (IVS1+6T/C); however, RT-PCR analysis indicated that the IVS+6C variant did not cause an aberrant splicing. Thus, the M832 variant could be a germline mutation causative of familial aggregation of DGC, although further functional studies are needed to understand the pathogenic significance of this variant.
authors.affiliation: Biology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yabuta
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.forename: Masachika
authors.initials: M
authors.lastname: Tani
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Kimio
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Erito
authors.initials: E
authors.lastname: Mochiki
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tsujinaka
authors.forename: Motohisa
authors.initials: M
authors.lastname: Takami
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hirose
authors.forename: Akio
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takenoshita
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection
chemical_list: D015820:Cadherins