Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability

Oncogene. 1998 Jul 16;17(2):157-63. doi: 10.1038/sj.onc.1201944.


Microsatellite instability occurs in 15% of colorectal carcinomas and may be due to replication errors (RER). The pattern of instability--'severe' vs 'mild'--and the tumorigenic pathway, as reflected by the involvement of functionally important genes, may vary according to the underlying gene(s). We defined 'mild' RER as mono- or tetranucleotide repeat instability in the absence of widespread instability at dinucleotide repeats and studied 15 colorectal tumors with this phenotype for mutations in the DNA mismatch repair genes MSH2, MLH1, MSH3, and MSH6. No mutations were found, suggesting that these genes were not implicated. We then compared colorectal cancers with 'mild' RER (n = 15), and those with 'severe' RER without (n = 11) or with (n = 22) detectable mutations in MSH2 or MLH1 to assess the involvement of mononucleotide repeats contained in the coding regions of MSH3, MSH6, BAX, and TGFbeta RII. The combined mutation rates of the above mentioned loci varied significantly between the three groups of tumors, being 0%, 25% and 52%, respectively. Furthermore, the individual genes showed specific patterns of involvement; for example, among tumors with 'severe' RER, TGFbeta RII displayed uniformly high mutation rates while MSH3, MSH6, and BAX were more frequently altered in tumors that also showed MSH2 or MLH1 mutations. Our findings suggest that different subcategories exist among unstable tumors, defined by the RER pattern on the one hand and tumorigenic pathway on the other, and structural changes of MSH2 and MLH1 are likely to explain only a proportion of these cases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Colorectal Neoplasms / classification
  • Colorectal Neoplasms / genetics*
  • DNA Repair*
  • DNA Replication / genetics
  • DNA, Neoplasm / metabolism*
  • DNA-Binding Proteins / genetics
  • Humans
  • Microsatellite Repeats*
  • Multidrug Resistance-Associated Proteins*
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • MutS Homolog 3 Protein
  • Mutagenesis / genetics*
  • Neoplasm Proteins / genetics
  • Nuclear Proteins
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • Transforming Growth Factor beta / genetics
  • bcl-2-Associated X Protein


  • Adaptor Proteins, Signal Transducing
  • BAX protein, human
  • Carrier Proteins
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • MSH3 protein, human
  • Multidrug Resistance-Associated Proteins
  • MutS Homolog 3 Protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transforming Growth Factor beta
  • bcl-2-Associated X Protein
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • multidrug resistance-associated protein 1