Analysis of microsatellite instability, protein expression and methylation status of hMLH1 and hMSH2 genes in gastric carcinomas.
OBJECTIVE
Microsatellite instability (MSI) is a manifestation of a defective DNA mismatch repair system. It is caused by germline mutations of mismatch repair genes or CpG islands hypermethylation. The majority of cancers of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have MSI+ phenotype. The colorectal cancers show distinctive clinicopathological characteristics and prognoses according to the MSI status. However, there is a wide variety of results between MSI and clinicopathological parameters in gastric carcinomas.


METHODS
Five hundred and twenty-one surgically resected gastric carcinomas were studied and the correlation with clinicopathological parameters, MSI status by using five microsatellite markers, expression of hMLH1 and hMSH2 protein by immunohistochemical stain, and methylation of hMLH1 and hMSH2 by methylation-specific polymerase chain reaction was analyzed.


RESULTS
There were 50 (9.6%) high-frequency MSI (MSI-H) cases. The MSI-H gastric carcinomas were associated with older age, expanding type by Ming's classification, lymphatic invasion, tumor multiplicity, losses of hMLH1 and hMSH2 protein expressions. The methylation frequency of hMLH1 was 75.5% in MSI-H gastric carcinomas.


CONCLUSIONS
Our results suggest that epigenetic inactivation of hMLH1 might play a role in the carcinogenesis of MSI-H gastric carcinomas. The immunohistochemical stain for hMLH1 protein expression could be used in routine diagnostic methods for predicting MSI status.
Gu
Mijin
M
Department of Pathology, Daegu Fatima Hospital, Daegu, Korea. kmjjws@naver.com
Kim
DongSun
D
Bae
YoungKyung
Y
Choi
JoonHyuk
J
Kim
SangWoon
S
Song
SunKyo
S
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000502:physiology*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein