The complex genotype-phenotype relationship in familial adenomatous polyposis

Familial adenomatous polyposis predisposes to colorectal cancer through multiple colorectal adenomas. The age of onset of adenomas and their number vary between families affected by this dominantly inherited trait, even within families. The same applies to a variety of associated manifestations including epidermoid cysts, osteomas, dental anomalies, desmoid tumours, retinal pigmentation and upper gastrointestinal polyps. The phenotype variation has a relationship with the site of truncating mutations on the APC gene. Thus, mutations at the mutation cluster region (codons 1250-1400) tend to cause early onset and severe polyposis whereas osteomas, dental changes and desmoids are most frequent in patients with the mutation 3' to codon 1400. The correlation observed, however, seems quite complex. Explanations may include variable interference of different mutant APC proteins on the wildtype APC function. There is also evidence suggesting an effect of modifier genes. The clinical applications of genotype-phenotype correlation on the management of patients with familial adenomatous polyposis remain limited apart from predictive genetic testing.