title: Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas.
abstract: OBJECTIVE
  To study the role of CDH1/E-cadherin (E-cad) gene alteration profiles including mutation, loss of heterozygosity (LOH), promoter polymorphism and hypermethylation in mechanisms of CDH1 inactivation in gastric carcinoma (GC).
  
  
  METHODS
  Specimens were collected surgically from 70 patients with GC. Allelotyping PCR and detection of LOH, denaturing high pressure liquid chromatography and DNA sequencing, restriction fragment length polymorphism analysis, methylation specific PCR, and immunohistochemical staining were used.
  
  
  RESULTS
  Promoter polymorphism was not a major mechanism of E-cad inactivation. Only one truncating mutation was found in a diffuse type tumor (3%). Both LOH and promoter hypermethylation were major mechanisms of E-cad inactivation, but interestingly, there was a negative association between the fraction of allelic loss (LOH) in tumors and hypermethylation of CDH1. Therefore LOH and hypermethylation were two different tumorigenic pathways involved in GC.
  
  
  CONCLUSIONS
  Given the findings that somatic mutation was extremely low and the relationship between LOH and hypermethylation was inverse, any two combinations of these three factors cannot fulfill the classical two-hit hypothesis of CDH1 inactivation. Thus, other mechanisms operating at the transcriptional level or at the post-translational level might be required to induce E-cadherin inactivation.
authors.affiliation: Division of General Surgery, Tri-Service General Hospital, No. 325, Sec 2, Cheng-Kung Road, Taipei, Taiwan, China. dlyaochi@yahoo.com.tw
authors.forename: Yao-Chi
authors.initials: YC
authors.lastname: Liu
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
authors.forename: Hurng-Sheng
authors.initials: HS
authors.lastname: Wu
authors.forename: Tsai-Yuan
authors.initials: TY
authors.lastname: Hsieh
authors.forename: De-Chuan
authors.initials: DC
authors.lastname: Chan
authors.forename: Cheng-Jueng
authors.initials: CJ
authors.lastname: Chen
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Yu
authors.forename: Horng-Jyh
authors.initials: HJ
authors.lastname: Harn
authors.forename: Peng-Jen
authors.initials: PJ
authors.lastname: Chen
authors.forename: Chung-Bao
authors.initials: CB
authors.lastname: Hsieh
authors.forename: Teng-Wei
authors.initials: TW
authors.lastname: Chen
authors.forename: Huan-Mieng
authors.initials: HM
authors.lastname: Hsu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: D015820:Cadherins