Distinct clinicopathologic and genetic profiles in sporadic gastric cancerwith different mutator phenotypes

A subset of sporadic gastric cancers (GC) exhibits microsatellite instabili ty (MSI). To define the precise role of MSI in GC, a total of 100 patients with sporadic GC were classified into three groups, i.e., high-frequency MS I (MSI-H), low-frequency MSI (MSI-L), and microsatellite stable (MSS), base d on 10 microsatellite markers. Mutational analyses of TGF beta R11, 1GFIIR , BAX, MSH3, MSH6, E2F4, MSH2, MLH1, and TP53 genes, and methylation and pr otein expression of MLH1 and MSH2 were performed and correlated. Twenty-sev en percent of GC showed MSI at least in one locus and could be further grad ed as MSI-H (14%) and MSI-L (13%). No clinicopathologic difference was note d between GC with MSI-L and MSS. Compared with GC with MSI-L or MSS, GC wit h MSI-H had a significantly higher frequency of antral location, intestinal subtype, H. pylori seropositivity, but a lower incidence of lymph node met astasis, and displayed a higher frequency of frameshift mutations of TGF be ta R11, 1GFIIR, BAX, MSH3, and E2F4 genes but a lower incidence of TP53 mut ations. Furthermore, hypermethylation of the MLH1 promoter was responsible for the loss of protein function in 13 of 14 MSI-H tumors. It was concluded that a specific phenotype and a distinct profile of genetic alterations ex ist in MSI-H GC. We speculate that epigenetic inactivation of MLH1 by methy lation plays a crucial role in initiating such a pathway of carcinogenesis. In contrast, GCs with MSS and MSI-L exhibit clinicopathologic features tha t are distinct from MSI-H tumors and have a higher frequency of TP53 mutati ons, suggesting that they may evolve through an entirely different pathway. (C) 2000 Wiley-Liss, Inc.