A genome-wide study of microsatellite instability in advanced gastric carcinoma.

Abstract

Microsatellite instability (MSI) has been described in many human carcinomas, including gastric carcinomas (GCs). There are inconsistent findings regarding the association of MSI with various subsets of GC with specific clinicopathologic features. The objective of this study was to define MSI in advanced GC at a genome-wide level and to evaluate the clinical relevance of MSI in these patients. Forty-one gastric adenocarcinomas with serosa invasion (T3) were analyzed at 59 loci that detected at least one site per arm of each autosome in human genome. The expression patterns of mismatch repair proteins hMLH1 and hMSH2 were examined by immunohistochemistry. Comparisons were made by categorizing tumors into three groups: tumors with MSI at multiple loci (at more than three loci), tumors with MSI at low level (at one to three loci), and microsatellite-stable (MSS) tumors. Clinical significance of MSI in advanced GC was evaluated. The relative rates of hypermutability of the 59 markers also were determined. A significant association was found between tumors with MSI at multiple loci and the expanding type of tumor growth by Ming's histologic classification (P = 0.001), whereas tumors with MSI at low level and MSS tumors are clinicopathologically indistinguishable. The 59 dinucleotide repeat markers displayed varying degrees of susceptibility toward genetic instability. The relative rates of hypermutability of these markers were consistent with a normal distribution pattern in which the frequency of unstable tumors detected at different chromosomal loci varied from 0% to 20%. The authors' results showed that advanced GC with MSI at multiple loci progress preferentially in an expanding mode, supporting the notion that high MSI tumors and low MSI/MSS tumors evolve through different genetic pathways. Thus, microsatellite testing may have clinical utility as a favorable prognostic marker.