Genetic and clinical characterisation of familial adenomatous polyposis: a population based study

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominantly inherited disease predisposing to colon cancer and caused by germline mutations in the APC (adenomatous polyposis coli) gene. AIMS: We conducted a population based study to evaluate the prevalence and clinical implications of APC mutations among Finnish FAP kindreds. A possible founder effect in parallel with previous observations in hereditary non-polyposis colon cancer (HNPCC) was addressed. PATIENTS: Affected individuals from 65 kindreds were included. METHODS: The APC gene was screened for mutations using the protein truncation test and heteroduplex analysis. Haplotype analysis was performed with four flanking microsatellite markers. Families that failed to show any mutations were scrutinised with Southern blot hybridisation and allelic expression analysis. RESULTS: Thirty eight different germline mutations in APC were identified in 47 kindreds (72%). The majority of these mutations were novel and unique to each family. Although sharing the classical polyposis phenotype, families without detectable APC mutations differed from mutation positive families in the following respects: firstly, mean age at polyposis diagnosis was higher (38.6 years (48 individuals) v 30.0 years (140 individuals); p=0.001); and secondly, the proportion of kindreds lacking extracolonic disease was higher (6/18 v. 5/47; p=0.04). CONCLUSIONS: Our results may pave the way for predictive testing in mutation positive families and should stimulate further molecular studies in mutation negative families. No founder effect was observed, which is in contrast with HNPCC in the same population.