title: Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population.
abstract: Germline point or small frameshift mutations of the CDH1 (E-cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1-bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation-dependent probe amplification (MLPA) and RT-PCR analyses, we also found a large genomic deletion (c.164-?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell-cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12- and Gly55fsX38-type CDH1 compared with cells expressing wild-type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC.
authors.affiliation: First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ito
authors.forename: Masako
authors.initials: M
authors.lastname: Kasami
authors.forename: Naomi
authors.initials: N
authors.lastname: Sasaki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shima
authors.forename: Masami
authors.initials: M
authors.lastname: Ikeda
authors.forename: Hong
authors.initials: H
authors.lastname: Tao
authors.forename: Masanori
authors.initials: M
authors.lastname: Goto
authors.forename: Takachika
authors.initials: T
authors.lastname: Ozawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tsuneyoshi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Tanioka
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D016466:CHO Cells; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion; D002460:Cell Line; D006224:Cricetinae; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007564:Japan; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins