Can APC: mutation analysis contribute to therapeutic decisions in familialadenomatous polyposis? Experience from 680 FAP families

Background and aims-In familial adenomatous polyposis (FAP), correlations b etween site of mutation in the adenomatous polyposis coli (APC) gene and se verity of colonic polyposis or extracolonic manifestations are well known. While mutation analysis is important for predictive diagnosis in persons at risk, its relevance for clinical management of individual patients is open to question. Methods-We examined 680 unrelated FAP families for germline mutations in th e APC gene. Clinical information was obtained from 1256 patients. Results-APC mutations were detected in 48% (327/680) of families. Age at di agnosis of FAP based on bowel symptoms and age at diagnosis of colorectal c ancer in untreated patients were used as indicators of the severity of the natural course of the disease. A germline mutation was detected in 230 of 4 04 patients who were diagnosed after onset of bowel symptoms (rectal bleedi ng, abdominal pain, diarrhoea). When these patients were grouped according to the different sites of mutations, mean values for age at onset of diseas e differed significantly: patients carrying APC mutations at codon 1309 sho wed a disease onset 10 years earlier (mean age 20 years) compared with pati ents with mutations between codons 168 and 1580 (except codon 1309) (mean a ge 30 years),whereas patients with mutations at the 5' end of codon 168 or the 3' end of codon 1580 were diagnosed at a mean age of 52 years. Within e ach group of patients however large phenotypic variation was observed, even among patients with identical germline mutations. A higher incidence of de smoids was found in patients with mutations between codons 1445 and 1580 co mpared with mutations at other sites, while no correlation between site of mutation and presence of duodenal adenomas was observed. Conclusions-As age at manifestation and course of the disease may be rather variable, even in carriers of identical germline mutations, therapeutic de cisions should be based on colonoscopic findings in individual patients rat her than on the site of mutation. However, in patients with mutations withi n codons 1445-1580, it may be advisable to postpone elective colectomy beca use desmoids may arise through surgical intervention.