Frequent alterations of the beta-catenin and TCF-4 genes, but not of the APC gene, in colon cancers with high-frequency microsatellite instability

J Exp Clin Cancer Res. 2001 Dec;20(4):553-9.


High-frequency microsatellite instability (MSI-H) due to defective DNA mismatch repair (MMR) is a characteristic of the majority of tumors from kindreds with hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic cancers. To better understand the molecular characteristics of colon cancers with MSI-H, we analyzed these cancers for alterations of genes, such as APC, beta-catenin, and TCF-4 genes, involved in the Wnt signaling pathway. Following the National Cancer Institute (NCI) criteria, 385 unselected colon cancers were classified as follows: 50 (13%) MSI-H tumors, 36 (9%) low-frequency MSI (MSI-L) tumors, and 299 (78%) microsatellite stable (MSS) tumors. The frequency of APC mutations was significantly lower in MSI-H tumors (9 out of 50) than in MSI-L (12 out of 20) and MSS (66 out of 100) tumors (P = 0.0005 and P < 0.0001, respectively). In contrast, the frequency of exon 3 mutations in the beta-catenin gene was higher in MSI-H tumors (10 out of 50) than in MSI-L tumors (0 out of 30; P = 0.0110) and MSS tumors (3 out of 100; P = 0.0010). Frameshift mutations in a (A)9 tract of the TCF-4 gene were detected in 44% (22 out of 50) of MSI-H tumors, but not in any of the 20 MSI-L tumors or 40 MSS tumors. In total, 78% of MSI-H tumors and 84% of the remaining tumors had at least one alteration in APC, beta-catenin, or the TCF-4 genes. Although further analysis is needed to functionally characterize the consequences of each of these alterations on beta-catenin/TCF target gene expression, our results suggest that the activation of the Wnt signaling pathway plays a pivotal role in colon tumorigenesis, irrespective of MSI status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Base Pair Mismatch / genetics
  • Colorectal Neoplasms / genetics*
  • Cytoskeletal Proteins / genetics*
  • DNA Primers / chemistry
  • DNA, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Genes, APC / physiology*
  • Humans
  • Immunoenzyme Techniques
  • Microsatellite Repeats / genetics*
  • Mutation / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins / physiology
  • Signal Transduction / genetics
  • TCF Transcription Factors
  • Trans-Activators / genetics*
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors / genetics*
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DNA Primers
  • DNA, Neoplasm
  • Proto-Oncogene Proteins
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Trans-Activators
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin