Mutational analyses of multiple target genes in histologically heterogeneous gastric cancer with microsatellite instability

Jpn J Cancer Res. 1998 Dec;89(12):1284-91. doi: 10.1111/j.1349-7006.1998.tb00525.x.


It has been recognized that gastric cancer often shows histological heterogeneity in a single tumor. Although microsatellite instability (MSI) has been reported in gastric cancer, the significance of genomic instability in gastric cancers with histological heterogeneity within a single tumor has never been addressed. We investigated MSI at 8 microsatellite loci in 40 normal/tumor DNA pairs from 20 gastric cancers with histological heterogeneity. Six of 20 patients (10 DNAs of 40 tumor DNAs) had severe MSI in more than 3 loci. Four of the MSI-positive cases had frameshift mutations in the poly(A)10 tract of the TGF beta RII gene. This mutation was found only in the MSI-positive component in the 2 cases (cases 4 and 5) in which only 1 component exhibited MSI. The other 4 cases demonstrated homozygous or heteroclonal mutations (1 and 2 base deletions) in the poly(A)8 tract of the hMSH3 gene; no mutation was detected in the poly(C)8 tract of the hMSH6 gene in any of the MSI-positive cases. The profile of alterations in multiple targets was different between the 2 components in most of the cases (5/6). These findings suggest that mismatch repair deficiency in MSI-positive tumors causes multiple gene inactivations through frameshift mutations in short repetitive sequences in a heterogeneous way within a histologically heterogeneous tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics*
  • DNA-Binding Proteins*
  • Female
  • Frameshift Mutation
  • Fungal Proteins / genetics*
  • Humans
  • Male
  • Microsatellite Repeats*
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Saccharomyces cerevisiae Proteins*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology


  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Fungal Proteins
  • MSH6 protein, S cerevisiae
  • Neoplasm Proteins
  • Receptors, Transforming Growth Factor beta
  • Saccharomyces cerevisiae Proteins
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II