Analysis of Microsatellite Instability, Protein Expression and Methylation Status of hMLH1 and hMSH2 in Gastric Carcinomas
MJ Gu, YK Bae, SW Kim, SK Song, DS Kim, JH Choi. Daegu Fatima Hospital, Daegu, Korea; Yeungnam University College of Medicine, Daegu, Korea; Kyungpook University College of Medicine, Daegu, Korea
Background: Microsatellite instability (MSI) is a manifestation of defective DNA mismatch repair system. The majority of cancers of hereditary non-polyposis colorectal cancer (HNPCC) syndrome have MSI+ phenotype. The CpG island methylation has been recognized as an alternative mechanism of gene inactivation in the carcinogenesis. Hypermethylation of hMLH1 mismatch repair gene has been revealed to lead the MSI in HNPCC. The colorectal cancers show distinctive clinicopathologic characteristics and prognosis according to the MSI status. However, there is a wide variety of results between MSI and clinicopathologic parameters in gastric carcinomas.
Design: To determine the correlation between MSI status and clinicopathologic characteristics in gastric carcinomas, five hundred twenty one gastric carcinomas by surgical resection were studied. We analyzed the correlation with clinicopathologic parameters, MSI status by using five microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250), expression of hMLH1 and hMSH2 protein by immunohistochemical stain, and methylation of hMLH1 and hMSH2 by methylation-specific polymerase chain reaction.
Results: In 521 cases, there were 50 (9.6%) high-frequency MSI (MSI-H) cases, 5 (1.0%) low-frequency MSI (MSI-L) cases, and 466 (89.4%) microsatellite stable (MSS) cases. In 50 MSI-H gastric carcinomas, the loss of hMLH1 and hMSH2 protein expression was 46 cases (92.0%) and 4 cases (8.0%), respectively. The MSI-H gastric carcinomas were significantly correlated with older age (50 years), expanding type of Ming's classification, lymphatic invasion, tumor multiplicity, and loss of hMLH1 protein expression (P<0.05). In MSI-H gastric carcinomas, the methylation frequency of hMLH1 and hMSH2 was 75.5% and 46.2%, respectively.
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 method for predicting MSI status.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 97, Tuesday Afternoon