MSI-L gastric carcinomas share the hMLH1 methylation status of MSI-H carcinomas but not their clinicopathological profile

Sporadic gastric carcinomas (SGC) with microsatellite instability (MSI) exh ibit mutations in target genes and display a particular clinicopathological profile. In SGC the MSI phenotype has been associated with hMLH1 promoter hypermethylation. Fifty-seven SGC, classified as high-frequency MSI (MSI-H) , low-frequency MSI (MSI-L), and microsatellite stable (MSS), were analyzed for hMLH1 promoter methylation status and clinicopathological features. hM LH1 mutations and hMLH1 expression, as well as target gene mutations, were also evaluated. Our aims were to characterize the molecular and clinicopath ological features of SGC, with and without hMLH1 promoter hypermethylation, and to compare the molecular and clinicopathological features of MSI-L, MS I-H, and MSS tumors in an attempt to clarify the place of MSI-L tumors in t he mismatch repair (MMR) pathway. Hypermethylation of hMLH1 promoter occurr ed in 27 of 57 SGC (47.3%) and was significantly associated with MSI status , target gene mutations, and expansive pattern of growth of the tumors. Sev enty-five percent of the MSI-H and 50% of MSI-L carcinomas showed hypermeth ylation (Met+) of hMLH1 in contrast to 0% in MSS carcinomas. No hMLH1 expre ssion was observed in MSI-L/Met+ and MSI-H/Met+ cases. MSS and MSI-L tumors share the same clinicopathological profile regardless of the methylation s tatus of the latter and are distinct from MSI-H tumors. We conclude that mu tations in target genes, more than hypermethylation or absence of expressio n of hMLH1, are the link between MSI status and most of the clinicopatholog ical features of SGC.