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In colorectal tumours, Wnt pathway genetics continues to be dominated by mutations in the adenomatous polyposis coli (APC) gene. Germline mutations cause familial adenomatous polyposis and at least two-thirds of sporadic colorectal tumours also acquire APC mutations, quite possibly as the initiating events in tumorigenesis. These mutations almost always cause loss of the C-terminal functions of the APC protein - probably involved in microtubule binding, cell polarity and chromosome segregation - and deletion of the SAMP repeats that are important for binding to axin and formation of the beta-catenin phosphorylation complex. The truncated APC proteins are, in general, stable and almost certainly retain some activity in beta-catenin binding. The 'two hits' at APC are coselected so as to produce an optimal activation of Wnt signalling (just-right hypothesis). In a minority of colorectal tumours, Wnt activation can occur through mutations that affect phosphorylation sites within exon 3 of beta-catenin, causing protein stabilization. In other tumours, epigenetic transcriptional silencing or mutation of the secreted frizzled-related proteins may modulate Wnt levels. Mutations in the Wnt components AXIN1, AXIN2 and TCF4 have been found in microsatellite-unstable colon cancers, but it is not clear in every case whether these changes are functional. Therapeutic modulation of the Wnt pathway remains an attractive therapeutic possibility for colorectal carcinomas.

Original publication

DOI

10.1038/sj.onc.1210059

Type

Journal article

Journal

Oncogene

Publication Date

04/12/2006

Volume

25

Pages

7531 - 7537

Keywords

Adenomatous Polyposis Coli, Animals, Axin Protein, Colorectal Neoplasms, Cytoskeletal Proteins, Gene Expression Regulation, Neoplastic, Genes, APC, Humans, Models, Biological, Mutation, Protein Structure, Tertiary, Repressor Proteins, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Wnt Proteins, beta Catenin