Immunohistochemical Analysis of Mismatch Repair Gene Proteins in Early Gastric Cancer Based on Microsatellite Status

Abstract

Background: Microsatellite instability (MSI) is a major pathway involved in gastric carcinogenesis and is observed in 10–20% of early gastric cancers (EGCs). Early detection of EGCs with an MSI-high phenotype would be useful for elucidating the mechanisms of gastric carcinogenesis and improving outcomes in patients with GC. Objective: We explored the usefulness of immunohistochemical expression of mismatch repair (MMR) proteins, including MLH1, PMS2, MSH2, and MSH6 in EGC. Methods: We examined the expression of 4 MMR proteins using immunohistochemistry in 119 patients with EGC based on MS status, as determined by polymerase chain reaction-microsatellite analysis. In addition, methylation of the MLH1 gene was quantified by pyrosequencing. Results: EGCs were classified into 46 MSI-high phenotypes and 73 microsatellite stable (MSS) phenotypes. Although loss of MLH1 expression was associated with loss of PMS2 expression in the MSI-high phenotype, discordant cases of loss of expression between MLH1 and PMS2 were found (MLH1 [−]/PMS2 [+], 3 cases). Loss of MLH1/PMS2 expression was observed in 2 of 73 MSS phenotypes. Loss of MSH2/MSH6 expression was found in 4 of 46 MSI-high phenotypes, whereas loss of MSH2/MSH6 expression was not detected in the MSS phenotype. In addition, loss of MLH1 expression was correlated with methylation of MLH1. However, there were discordant cases in which loss of MLH1 expression was not accompanied by methylation of MLH1. Conclusion: Although immunostaining of MMR proteins could help predict MSI in EGCs, immunostaining did not have the same value as genetic testing for determination of MSI.