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

Am J Pathol. 1998 Oct;153(4):1211-9. doi: 10.1016/s0002-9440(10)65665-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aged
  • DNA Primers / chemistry
  • DNA Repair
  • DNA Replication
  • DNA, Neoplasm / analysis
  • DNA, Satellite / analysis
  • Female
  • Genetic Markers
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Male
  • Microsatellite Repeats / genetics*
  • Middle Aged
  • Mutation*
  • Prognosis
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-bcl-2*
  • Receptor, IGF Type 2 / genetics*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • bcl-2-Associated X Protein

Substances

  • BAX protein, human
  • DNA Primers
  • DNA, Neoplasm
  • DNA, Satellite
  • Genetic Markers
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptor, IGF Type 2
  • Receptors, Transforming Growth Factor beta
  • bcl-2-Associated X Protein
  • Hypoxanthine Phosphoribosyltransferase
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II