The discovery of the molecular basis of FAP by identification of germline mutations in the APC gene in polyposis patients has stimulated the interest of clinicians and molecular biologists in this disease. During the last years several groups of polyposis patients have been examined for mutations in the APC gene. APC mutation detection rates in FAP patients varying between 30-85% have been published. This variation largely depends on patient selection and their clinical phenotype: the discovery that attenuated FAP is also caused by germline mutations in the APC gene has increased the proportion of patients with few adenomas irrespective of the family history among patients examined for mutations. This has led to an overall decrease in the mutation detection rate. Our data show mutation detection rates up to 85% when patients with typical FAP are considered.
Impressive correlations between the site of mutations in the large APC gene and the clinical phenotype including both the colonic polyposis phenotype and manifestation of extracolonic features have been published. Examination for CHRPE had been proposed as a useful marker for pointing to the gene region that should be examined for APC mutations. In addition, CHRPE status was thought to be used for predictive testing in families with no identified APC mutation, but where the index patient presents with CHRPE. However, findings of intrafamilial discrepancies in CHRPE status limit its use as a predictive marker in persons at risk. Moreover, due to the absence of CHRPE in most patients with an attenuated polyposis phenotype, ophthalmogical examinations are of little value in the actual diagnostic procedure.
The association of attenuated FAP with APC mutations localised in the 5' or 3' part of the gene or in the alternatively spliced region of exon 9 has also repeatedly been published and has been, in principle, confirmed in our sample of 1379 patients with known APC mutations. When examining this correlation it should be kept in mind that classification of the clinical phenotype into typical and attenuated FAP may be difficult in some cases. This classification is based ideally on the age at onset of polyp growth and age-related polyp numbers, but in most cases these data are not available because patients are diagnosed at different stages of disease development. On the other hand, the type of mutation may also play a role and may explain some exceptions to the expected relationship. In addition, even intrafamilial variation of the clinical phenotype has been described, pointing to the presence of other genetic or environmental factors. Therefore, identification of the APC mutation in a patient is of limited value for the prediction of the clinical course of the disease or for therapeutic decisions.
The discovery of MUTYH-associated polyposis (MAP) due to biallelic mutations in the MUTYH gene has complicated our perception of adenomatous polyposis. Initially it was thought that all cases of adenomatous polyposis follow an autosomal-dominant mode of inheritance and are caused by mutations in the APC gene, irrespective of whether or not the mutation was identified. The existence of an autosomal-recessive polyposis disease that clinically resembles FAP implies that some statements regarding risk predictions in the families based on indirect genotype analysis or apparent de novo mutations have to be reevaluated. The frequency of MUTYH-associated polyposis among unselected APC-mutation-negative polyposis patients ranges between 15% and 40%.
In this context the search for an APC mutation, especially in patients without a family history of FAP, is of importance for defining the recurrence risk in their families. However, mutation analysis is still laborious and expensive, and even with more up-to-date and sophisticated methods a mutation in the APC (or MUTYH) gene(s) cannot be excluded. Moreover, as other polyposis syndromes (e.g. familial juvenile polyposis or Peutz Jeghers syndrome, caused by mutations in other genes) have to be considered as differential diagnoses, we would like to emphasise the importance of the clinical diagnosis including polyp number, site of location in the colorectum and histology, and family history prior to requesting molecular diagnostics. These data, especially polyp histology, are necessary in order to differentiate between different types of polyposis and to provide mutation analysis of the appropriate genes.
The identification of the underlying germline mutation(s) in polyposis patients allows predictive diagnostics in persons at risk in their families. Genetic counselling should be offered to the patients and their families in order to explain the complex picture of polyposis disease, including the possibilities and limitations of molecular diagnostics for surveillance and therapy.
Supplementary table 1. 315 different point mutations detected in 597 out of 1166 unrelated patients suspected of FAP. (The DNA mutation numbering is based on the cDNA sequence for APC where +1 corresponds to the A of the ATG translation initiation codon (more ...)
Supplementary table 2. Large deletions detected in 37 out of 1166 unrelated patients suspected of FAP