Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas.
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.
Liu
Yao-Chi
YC
Division of General Surgery, Tri-Service General Hospital, No. 325, Sec 2, Cheng-Kung Road, Taipei, Taiwan, China. dlyaochi@yahoo.com.tw
Shen
Chen-Yang
CY
Wu
Hurng-Sheng
HS
Hsieh
Tsai-Yuan
TY
Chan
De-Chuan
DC
Chen
Cheng-Jueng
CJ
Yu
Jyh-Cherng
JC
Yu
Cheng-Ping
CP
Harn
Horng-Jyh
HJ
Chen
Peng-Jen
PJ
Hsieh
Chung-Bao
CB
Chen
Teng-Wei
TW
Hsu
Huan-Mieng
HM
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*
D015820:Cadherins