Differential clinicopathologic features in microsatellite-unstable gastric cancers with and without MLH1 methylation

Key clinicopathologic features of microsatellite instability-positive (MSI+) gastric cancers (GCs) are that they tend to be located in the antrum and have an intestinal phenotype and an expanding-type growth pattern. They are also associated with a better prognosis. Although MSI occurs mainly as a result of promoter CpG island hypermethylation in the mismatch repair gene MLH1, only a minority of MSI+ GCs develop from genetic mutations of mismatch repair enzymes, including MLH1 and MSH2. Furthermore, it is unknown whether there are differences in the clinicopathologic features of MSI+ GCs with and without MLH1 methylation. The methylation status of 17 genes (including MLH1) was assessed in 102 cases of MSI+ GC to determine whether there was a correlation between the clinicopathologic/molecular features of MSI+ GC and MLH1 methylation status. Compared with MSI+ GCs without MLH1 methylation (n = 22), MSI+ GCs with MLH1 methylation (n = 80) had an older age of onset (66.9 versus 60.9 years, P = .018), were more frequently located in the antrum (86.3% versus 50%, P = .001), exhibited an ulcerofungating gross type of tumor morphology (50.0% versus 9.1 %, P < .001), and had a higher number of unstable microsatellite loci (4.7 versus 3.8, P < .001) and a higher number of methylated genes (11.4 versus 6.2, P < .001). In addition, MLH1-deficient tumors without MLH1 methylation were associated with a better clinical outcome than MLH1-deficient tumors with MLH1 methylation or tumors that retained expression of both MLH1 and MSH2 (P = .002). These findings suggest that MSI+ GCs with and without MLH1 methylation may have different clinicopathologic features. Furthermore, some of the known clinicopathologic features of MSI+ GC, including older age of onset, ulcerofungating gross morphology, and antral location, are not typical of MSI+ GC without MLH1 methylation.