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Frequent frameshift mutations of the TCF-4 gene in colorectal cancers with microsatellite instability

A Duval1, J Gayet, X P Zhou

  • 1INSERM U434-Centre d'Etude de Polymorphisme Humane, Paris, France.

Cancer Research
|September 15, 1999
PubMed

Insights

Microsatellite instability-high (MSI-H) colorectal cancers frequently harbor TCF-4 gene mutations. These TCF-4 frameshift mutations likely contribute to MSI-H tumor development and progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Approximately 15% of sporadic colorectal cancers exhibit microsatellite instability (MSI), classified as MSI-H tumors, often due to mismatch repair gene inactivation.
  • Known MSI-H tumor progression involves frameshift mutations in genes like TGFbeta-RII, BAX, and IGFRII.
  • The TCF-4 gene, a key component of the Wnt/beta-catenin pathway, is investigated as a potential target in MSI-H tumorigenesis.

Purpose of the Study:

  • To investigate the frequency and role of mutations in the TCF-4 gene within MSI-H colorectal tumors.
  • To determine if TCF-4 mutations are specific to MSI-H colorectal cancer and contribute to its development.

Main Methods:

  • Analysis of TCF-4 gene coding region, specifically an (A)9 repeat, in human MSI-H colorectal cell lines and primary tumors.
  • Comparison of mutation rates in MSI-H samples versus non-MSI colorectal tumors and cell lines.
  • Examination of the functional consequences of TCF-4 mutations on protein isoforms and transcriptional activity.

Main Results:

  • Frameshift mutations, specifically a 1-bp deletion in an (A)9 repeat, were identified in 50% of MSI-H colorectal cell lines and 39% of MSI-H primary tumors.
  • Such mutations were rare in non-MSI colorectal tumors (1 of 56) and absent in non-MSI cell lines (0 of 16).
  • These findings suggest TCF-4 mutations are selected for in MSI-H colorectal tumorigenesis.

Conclusions:

  • TCF-4 frameshift mutations are frequent in MSI-H colorectal cancers and are likely selected during tumor development.
  • Mutations in the TCF-4 (A)9 repeat may alter protein isoform balance, impacting TCF-4's role in colorectal tumorigenesis.
  • TCF-4 represents a significant target gene for instability in MSI-H colorectal cancer progression.

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