The clinicopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different "target genes": a study of the TGFbeta RII, IGFII R, and BAX genes

Abstract

Gastric carcinomas with DNA replication errors (RER phenotype) display a particular clinicopathologic profile and carry a putative favorable prognosis. The RER phenotype has been identified as microsatellite instability in noncoding regions, as well as in repeat sequences within exons of several "target genes": TGFbeta RII, IGFII R, and BAX. In an attempt to find out whether the RER status is a significant prognostic factor in gastric carcinoma in a multivariate analysis and whether the clinicopathological features of the RER+ tumors are associated with mutations in the "target genes," we evaluated a series of 152 cases of sporadic gastric carcinoma. Five or six microsatellite loci and/or BAT 26, a poly(A) tract, were analyzed in each case using polymerase chain reaction and electrophoresis. Thirty-five cases (23.0%) were RER+. The RER phenotype was closely associated with a low pTNM stage and carried a significantly better prognosis. The repeat sequences of the target genes were screened for mutations in 28 RER+ and 13 RER-tumors. Mutations in TGFbeta RII occurred in 67.9% of the RER+ tumors and were significantly associated with the glandular histotype. IGFII R and BAX mutations occurred, respectively, in 25.0% and 32.1% of the cases; there was a trend toward an association between mutations in these genes and decreased nodal metastization and wall invasiveness, respectively. We conclude that the RER status is a significant prognostic indicator in gastric carcinoma and that such prognostic influence may be mediated by mutations in TGFbeta RII, IGFII R, and BAX genes.

Figure 1.

A: Example of a case with stable alleles with BAT 26 analysis. B: Examples of cases with unstable shortened alleles in RER+ gastric carcinomas.

Figure 2.

Survival curves of patients with RER+ (n = 31) and RER− (n = 108) gastric carcinomas. For details see text.

Figure 3.

Representative examples of frameshift mutations detected in mononucleotide tracts of the various coding regions. T, tumor; N, normal. A: Mutations within the poly(A)₁₀ tract of TGFβ RII. B: Mutations within the poly(G)₈ tract of IGFII R. C: Mutations within the poly(G)₈ tract of BAX.