Colorectal cancer and genetic alterations in the Wnt pathway
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.
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Loss of heterozygosity of APC is one of the earliest and rate-limiting events in the progression from normal epithelium to adenoma formation and then cancer.
“loss of heterozygosity (LOH) of APC has been shown to be one of the earliest and rate-limiting events in the progression from normal epithelium to adenoma formation and then cancer [3–5].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [5]
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- Authors
- Segditsas, S., & Tomlinson, I.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Tomlinson, I
- ORCID
- Tomlinson, I
- Venue
- Oncogene
- Published
- 2006-12-04
- Volume
- 25
- Issue
- 57
- Pages
- 7531-7537
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2072573412
- Cited by
- 591
- References
- 0
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 15 · 2023: 19 · 2022: 18 · 2021: 22 · 2020: 36 · 2019: 34 · 2018: 26 · 2017: 33 · 2016: 36 · 2015: 39 · 2014: 35 · 2013: 34 · 2012: 32
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- colorectal cancer, Wnt signaling, APC mutation, familial adenomatous polyposis, β-catenin, two-hit hypothesis, AXIN1, Axin2, TCF4, microsatellite instability, secreted frizzled-related proteins, epigenetic silencing, carcinogenesis
- MeSH terms
- Animals, Cytoskeletal Proteins, Humans, Models, Biological, Mutation, Adenomatous Polyposis Coli, Repressor Proteins, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Protein Structure, Tertiary, Genes, APC, Wnt Proteins, beta Catenin, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Axin Protein
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