ReviewThe adenomatous polyposis coli (APC) tumour suppressor – genetics, function and disease
Section snippets
The APC gene
APC (chromosome 5q21) comprises 16 translated exons and encodes a 2861 aa protein that is expressed in specific (frequently post-replicative) epithelial and mesenchymal cells of several fetal and adult human tissues (Table 1)1., 2.. The APC protein occurs in multiple forms varying in molecular weight from approximately 90–300 kDa (Fig. 1)3., 4.. This variation probably arises from alternative splicing at the mRNA level, although post-translational modifications and degradation may also play a
The structure of the APC protein
The large APC protein comprises several functional domains (Fig. 1). Heptad repeats at the amino-terminal end (aa 6–57) mediate APC homodimer formation1., 9.. Amino acids 453 to 767 show some homology to the central repeat region of the Drosophila segment polarity protein armadillo. This domain binds to APC-stimulated guanine nucleotide exchange factor (Asef), thereby enhancing the interaction of Asef with Rac (a member of the Rho family of small GTPases) that controls cell adhesion and
Regulation of β-catenin
β-catenin is involved in both the E-cadherin cell-adhesion system and the Wnt-1 signalling pathway. APC functions as a negative regulator of β-catenin levels26., 27.: it forms a complex with axin, which recruits β-catenin and facilitates GSK3-β phosphorylation of β-catenin at several serine–threonine residues; this targets the protein for ubiquitination by β-transducin repeat-containing protein (β-TRCP) with subsequent proteasomal degradation (Fig. 2)28., 29.. Phosphorylation of both APC and
Disease phenotypes associated with germline mutations of the APC gene
Germline mutations in the APC gene cause FAP, and somatic mutations occur in FAP tumours and sporadic colorectal tumours. FAP is an autosomal dominant predisposition to colorectal cancer affecting approximately 1:13 500 individuals42. The most prominent clinical manifestation is hundreds to thousands of colorectal polyps. Germline mutations throughout the APC gene have been described in the disease, which differ in their penetrance, severity of polyposis and the expression of extra-colonic
Somatic mutations in the APC gene
In most FAP tumours, the second allele of APC is either disrupted by another mutation, or, less frequently, lost. Consequently APC has been defined as a tumour suppressor gene. Consistent with this definition is the observation that most sporadic colorectal cancers also carry two inactivating APC mutations62. The mutation of both APC alleles appears to be the initial step in colorectal tumorigenesis in FAP and, in this context, APC can be classified as a gatekeeper gene63., 64.. Inactivation of
Associations between germline and somatic APC mutations
Analysis of somatic mutations including allelic loss in early colorectal adenomas of AAPC and FAP patients reveals an interesting correlation with the position of the APC germline mutation. Germline mutations around codon 1300 are associated with loss of the wild-type APC allele. By contrast, patients with germline mutations 3′ and 5′ to this region predominantly show truncating ‘second hits’ in the mutation cluster region65. A very similar association exists between the ‘two hits’ at APC in
APC and β-catenin mutations
Mutations in either β-catenin or APC are known to lead to tumorigenesis, yet the majority of colorectal tumours harbour APC mutations67. Although there is no evidence that germline β-catenin mutations predispose to colo-rectal tumours, some bowel cancers have somatic mutations in exon 3 of β-catenin and have no APC mutations68., 69.. These β-catenin mutations alter GSK3β phosphorylation sites and thus prevent β-catenin degradation. Colorectal cancers with β-catenin mutations tend to be MSI+ and
General models of APC function in colorectal tumorigenesis
Despite the advances in identifying functional domains of APC, the consequences of APC mutations for protein function and disease phenotype are not yet well understood. Several models have been described that attempt to explain how APC mutations lead to the growth of colo-rectal tumours. On current evidence, no single model can explain all the observed data, and the truth could lie in some combination of models.
Selective loss of function
The usual model of tumour suppressor mutation is one of simple loss of function. In keeping with this model, most colorectal cancers have biallelic mutation or allelic loss at APC and missense mutations are rare. However, the existence of the MCR, the association between first hits and second hits, the existence of third hits, the relatively low frequency of allele loss at APC, the mild disease associated with germline mutations causing absent protein, and the low frequency of colorectal
Concluding remarks
There remain several outstanding questions concerning the role of APC in FAP. For example, despite the identification of new functions of APC we still do not fully understand the normal role/roles of this protein and the relevance of the various APC functions to tumorigenesis. We still do not know why mutation in this seemingly important tumour suppressor is only manifest in a few tissues, and with such particularly severe outcome in the large bowel.
To enable more accurate prediction of the
Acknowledgements
OS is supported by the Boehringer Ingelheim Funds; HL and IT are supported by the Imperial Cancer Research Fund.
Glossary
- Adenomatous polyp
- A benign epithelial tumour in which the cells form recognizable glandular structures or in which the cells are clearly derived from glandular epithelium.
- Germline mutation
- An inherited mutation being present in all cells of the organism.
- Oncogene
- A gene involved in the control of cell proliferation, which, when overactive, can help to transform a normal cell into a tumour cell.
- Penetrance
- The likelihood, or probability, that a condition or disease phenotype will appear when a given
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Cited by (107)
The genetic factors associated with Wnt signaling pathway in colorectal cancer
2020, Life SciencesCitation Excerpt :In classical FAP, the average age for an individual to develop CRC is reported to be approximately 39 years old, along with a high incidence of adenomatous polyps and germline mutations between codons 168 and 1680. In this manner, the mutations between codons 1250 and 1464, particularly codon 1300, are linked to the maximum number of polyps with an estimated rate of 100% lifetime risk for developing invasive tumors [59,62,68,69]. In attenuated adenomatous polyposis coli (AAPC), a variant of FAP disease, the colonic adenomas are less than 100 and usually occur in those who are older than 40 years.
Role of adenomatous polyposis coli (APC) gene mutations in the pathogenesis of colorectal cancer; current status and perspectives
2019, BiochimieCitation Excerpt :Most cases of FAP are due to germ-line mutations in the APC gene, resulting in a chromosomal instability (CIN) phenotype of tumors (Fig. 1) [15]. Based on the age of onset of the disease and the number of colorectal Adenomatous polyps, FAP, is divided into two classes: 1) the classical FAP (CFAP) in which the average age of developing a tumor is 39 years and patients develop thousands of Adenomatous polyps in the colorectal region with 100% lifetime risk for developing to invasive carcinoma [16], and 2) attenuated FAP (AFAP, also called attenuated Adenomatous Polyposis Coli or AAPC) which the occurrence of colonic adenomas are <100 and average age of onset is > 40 [17,18]. APC protein is a component of the Wnt signaling pathway [19].
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