Microsatellite instability (MSI) is known to result from inactivation of mismatch repair genes largely by promoter methylation. However, the methylation usually accumulates time-dependently. To know whether MSI can be acquired later in tumorigenesis, we examined intratumoral heterogeneity of MSI and promoter methylation of hMLH1 after immunohistochemical screening for heterogeneous expression of hMLH1 in 55 cases of gastric carcinomas. We demonstrated for the first time that MSI-H can develop from MSI-L or the absence of MSI due to time-dependent accumulation of DNA methylation during progression of early-stage gastric carcinomas. The resultant replication errors may play a role in enhancing invasive activity.
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