The APC gene in colorectal cancer

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Abstract

Mutations in the adenomatous polyposis coli (APC) gene are not only responsible for familial adenomatous polyposis (FAP), but also play a rate-limiting role in the majority of sporadic colorectal cancers. Colorectal tumours are known to arise through a gradual series of histological changes, the so-called ‘adenoma–carcinoma’ sequence, each accompanied by a genetic alteration in a specific oncogene or tumour suppressor gene. Loss of APC function triggers this chain of molecular and histological changes. In general, an intestinal cell needs to comply with two essential requirements to develop into a cancer: it must acquire selective advantage to allow for the initial clonal expansion, and genetic instability to allow for multiple hits at other genes responsible for tumour progression and malignant transformation. Inactivation of APC seems to fulfill both requirements. In this short review, I will discuss the role played by APC in providing, when mutated, selective advantage, through constitutional activation of the Wnt signal transduction pathway, and chromosomal instability to the nascent intestinal tumor cell.

Introduction

Colon cancer is one of the most common malignancies among populations in the US and Western Europe, and one of the leading causes of worldwide morbidity and mortality due to cancer. In the US, approximately 140 000 new cases and 50 000 deaths are registered each year [1]. In Europe, each year about 213 000 new cases and 110 000 deaths are reported, respectively [2] (see also: http://www-dep.iarc.fr). The lifetime colorectal cancer risk in the general population is 5%, but this figure rises dramatically with age: by the age of 70 years, approximately half the Western population will have developed an adenoma. In general, the incidence of colorectal cancer is high in developed countries, with incidence rates varying up to 20-fold between high- and low-risk geographical areas throughout the world [2]. These variations in colorectal cancer incidence are likely to result from environmental and mainly dietary modifying factors.

Colorectal carcinomas arise through a series of well-characterised histopathological changes as the result of specific genetic ‘hits’ at a few oncogenes and tumour suppressor genes. At least four sequential genetic changes need to occur to ensure colorectal cancer evolution (Fig. 1). One oncogene (KRAS) and three tumour suppressor genes (adenomatous polyposis coli (APC), SMAD4 and TP53) are the main targets of these genetic changes. In particular, loss of APC gene function seems to trigger the cascade of events that eventually leads to malignant transformation in the large bowel. Here, I will focus on the function of the APC gene in homeostasis and cancer, as this knowledge is expected to provide the basis for the development of future tailor-made preventive and therapeutic interventions for colorectal cancer.

Section snippets

The APC gene in homeostasis and cancer

The APC gene was initially identified by positional cloning of the FAP (familial adenomatous polyposis) locus 3, 4. Subsequently, the majority of sporadic colorectal tumours were found to harbour mutations in both APC alleles 5, 6. Initially, the sequence of the large (312 kDa) APC protein did not allow specific predictions about its intracellular function. The first functional clues were provided by the identification of β-catenin as a binding partner of APC 7, 8. β-catenin was originally

A genetic model for APC-driven colorectal tumorigenesis

A general picture is emerging from the analysis of the essential roles of the Wnt signal transduction pathway in providing selective advantage to the nascent tumour cell, and in exerting genetic instability to ensure both tumour progression and malignant transformation: the APC gene, because it encompasses both functions, plays a central initiating and promoting role in colorectal cancer. Its inactivation and the resulting constitutive activation of the Wnt pathway provides a strong selective

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