Abstract
The autosomal-dominant precancerous condition familial adenomatous polyposis (FAP) is caused by germline mutations in the tumour suppressor gene APC. Consistent correlations between the site of mutations in the gene and clinical phenotype have been published for different patient groups. We report our experiences of APC mutation analysis and genotype-phenotype correlations in 1166 unrelated polyposis families and discuss our results in the light of literature data. We show that the mutation detection rates largely depend on the family history and clinical course of the disease. We present a list of 315 different point mutations and 37 large deletions detected in 634 of the 1166 index patients. Our results confirm previously published genotype-phenotype correlations with respect to the colorectal phenotype and extracolonic manifestations. However, 'exceptions to the rule' are also observed, and possible explanations for this are discussed. The discovery of autosomal-recessive MUTYH-associated polyposis (MAP) as a differential diagnosis to FAP implies that some results have to be reinterpreted and surveillance guidelines in the families have to be reevaluated.
Highlights
Familial adenomatous polyposis (FAP, OMIM+175100) is a clinical diagnosis that is typically based on the presence of more than 100 colorectal adenomas.If untreated patients develop colorectal cancer at a mean age of 40 years [1]
Germline mutations in the APC gene were detected in some families with an attenuated polyposis phenotype (AAPC, AFAP) who present with less than 100 adenomas and a later age at onset compared to patients with typical familial adenomatous polyposis (FAP) [6]
In this review we report on our experience of mutation analysis in the APC gene and genotype-phenotype correlations in 1166 unrelated patients with a clinical diagnosis of FAP or multiple adenomatous polyposis consistent with AAPC and discuss our results in the light of literature data
Summary
Familial adenomatous polyposis (FAP, OMIM+175100) is a clinical diagnosis that is typically based on the presence of more than 100 colorectal adenomas.If untreated patients develop colorectal cancer at a mean age of 40 years [1]. Germline mutations in the APC gene were detected in some families with an attenuated polyposis phenotype (AAPC, AFAP) who present with less than 100 adenomas and a later age at onset compared to patients with typical FAP [6]. During the last few years correlations between site of mutation in the APC gene and clinical phenotype have been reported on patient groups of different sizes
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