title: Frequent frameshift mutations of the TCF-4 gene in colorectal cancers with microsatellite instability.
abstract: About 15% of sporadic colorectal cancers show microsatellite instability (MSI) due to the inactivation of mismatch repair genes and are termed MSI-H tumors. In these tumors, frameshift mutations in coding repeats have been found within the TGFbeta-RII, BAX, and IGFRII genes that are probably involved in their progression. In the present work, we report frequent mutations in TCF-4, another target gene for instability. TCF-4 codes for a transcription factor that is a crucial member of the adenomatous polyposis coil (APC)/beta-catenin/T-cell factor (TCF) pathway. Fifty percent (4 of 8) of human MSI-H colorectal cell lines and 39% (19 of 49) of MSI-H colorectal primary tumors were found to have a 1-bp deletion in an (A)9 repeat within the coding region of this gene. In contrast, a frameshift mutation was found in only 1 of 56 non-MSI colorectal tumors and in none of 16 non-MSI colorectal cancer cell lines. These results suggest that TCF-4 frameshift mutations are selected for and play a role in colorectal MSI-H tumorigenesis. Depending on different reading frames due to alternatively spliced TCF-4 mRNA, the (A)9 repeat normally codes for several isoforms that could serve as modulators of TCF-4 transcriptional activity. The deletion of one nucleotide in this repeat could change TCF-4 transactivating properties by modifying the respective proportions of the different isoforms.
authors.affiliation: INSERM U434-Centre d'Etude de Polymorphisme Humane, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Duval
authors.forename: J
authors.initials: J
authors.lastname: Gayet
authors.forename: X P
authors.initials: XP
authors.lastname: Zhou
authors.forename: B
authors.initials: B
authors.lastname: Iacopetta
authors.forename: G
authors.initials: G
authors.lastname: Thomas
authors.forename: R
authors.initials: R
authors.lastname: Hamelin
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D016368:Frameshift Mutation; D017491:Genes, APC; D006801:Humans; D018895:Microsatellite Repeats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin