Review
The adenomatous polyposis coli (APC) tumour suppressor – genetics, function and disease

https://doi.org/10.1016/S1357-4310(00)01828-1Get rights and content

Abstract

Mutations in the adenomatous polyposis coli (APC) gene are the basis of familial adenomatous polyposis and the majority of sporadic colorectal cancer. APC is expressed in a wide variety of tissues, interacts with the cytoskeleton, is involved in regulating levels of β-catenin and, most recently, has been shown to bind DNA, suggesting that it may possess a nuclear role. The mutation spectrum implicated in tumorigenesis and its correlation with disease phenotype is well characterized and has contributed to our understanding of important functional domains in APC. Despite these advances, APC continues to provide a fertile subject of research for both colorectal tumorigenesis and cancer in general.

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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