Colorectal cancer and genetic alterations in the Wnt pathway.
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.
Segditsas
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S
Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK.
Tomlinson
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I
D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000818:Animals; D060466:Axin Protein; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C555451:AXIN1 protein, human; C491761:AXIN2 protein, human; D060466:Axin Protein; D003598:Cytoskeletal Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin