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Colorectal cancer and genetic alterations in the Wnt pathway.
Oncogene. 2006 Dec 04; 25(57):7531-7.O

Abstract

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.

Authors+Show Affiliations

Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK.No affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

17143297

Citation

Segditsas, S, and I Tomlinson. "Colorectal Cancer and Genetic Alterations in the Wnt Pathway." Oncogene, vol. 25, no. 57, 2006, pp. 7531-7.
Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006;25(57):7531-7.
Segditsas, S., & Tomlinson, I. (2006). Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene, 25(57), 7531-7.
Segditsas S, Tomlinson I. Colorectal Cancer and Genetic Alterations in the Wnt Pathway. Oncogene. 2006 Dec 4;25(57):7531-7. PubMed PMID: 17143297.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Colorectal cancer and genetic alterations in the Wnt pathway. AU - Segditsas,S, AU - Tomlinson,I, PY - 2006/12/5/pubmed PY - 2007/1/4/medline PY - 2006/12/5/entrez SP - 7531 EP - 7 JF - Oncogene JO - Oncogene VL - 25 IS - 57 N2 - 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/17143297/Colorectal_cancer_and_genetic_alterations_in_the_Wnt_pathway_ L2 - https://doi.org/10.1038/sj.onc.1210059 DB - PRIME DP - Unbound Medicine ER -