Genotype-phenotype correlations at the adenomatous polyposis coli (APC) gene

Germline mutations at the adenomatous polyposis (APC) gene are responsible for familial adenomatous polyposis (FAP), an inherited condition that predisposes to the development of hundreds to thousands benign adenomas in the colorectum. If not surgically removed, colorectal adenomas inevitably progress into malignant adenocarcinomas. To date, more than 450 germline mutations have been described at the APC gene, allowing the establishment of genotype-phenotype correlations between the site and type of the molecular defects and their morbid consequences. However, the function of the APC protein and its role in intestinal tumorigenesis are still elusive. Somatic mutations in the APC gene have also been found in the majority of early sporadic adenomas with similar frequencies as those reported in the more advanced colorectal tumors, clearly indicating that it represents an important determinant in the pathogenesis of this common cancer. Therefore, studies on the normal function of APC and the mechanisms by which its tumorigenic mutations lead to the development of cancer would have practical (i.e., clinical) as well as theoretical relevance. Here, we review the current literature on the relationship between APC mutations and their phenotypic consequences, with particular regard of the implications for the understanding of the function of this gene in homeostasis and tumorigenesis.