Correlation between APC germline mutation and clinical phenotyoe in familial adenomatous polyposis *
Background : Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by the occurrence of multiple colorectal adenomatous polyps and various extracolonic manifestations. The gene responsible for FAP is the adenomatous polyposis coli (APC) gene. To investigate the clinical significance of the APC gene analysis in the disease, I searched for APC germline mutations in our FAP patients, and compared them with clinical manifestations. Subjects and methods : The subjects were 44 FAP patients from 32 families. The APC gene in these subjects was screened by polymerase chain reaction based-single strand conformation polymorphism or the protein truncation test. The patients were divided into a 5' mutation group (exons 1-13), a 3' mutation group (exon 15) and a negative group. The types of colorectal polyposis, the frequencies of gastroduodenal adenomatosis and extraintestinal manifestations (osteoma, desmoid tumors, congenital hypertrophy of the retinal pigment epithelium), and the clinical course of duodenal adenomatosis were compared among the three groups. In the 3' and 5' mutation groups, the mutation was further determined by sequencing analysis. Results : Eight patients from 7 families had a 5' mutation and 22 from 11 families had a 3' mutation. The remaining 14 patients from 14 families were negative for APC gene mutation. The prevalence of profuse polyposis, duodenal adenomatosis and congenital hypertrophy of the retinal pigment epithelium were significantly higher in the 3' mutation group than in the 5' mutation group and the negative group. However, there was no difference in the prevalence of progressive duodenal adenomatosis. Fifteen different mutations were detected in 16 families. Eight mutations in eight families were nonsense mutations, while seven in eight families were frameshift mutations. Three families with mutations at codons 161, 332 and 1556 had sparse colorectal adenomatosis with serrated adenoma. A family with a mutation at codon 1556 had severe and progressive duodenal adenomatosis. A family member with a mutation at codon 1530 had severe desmoid tumors. Conclusion : There is a close correlation between genotypic and phenotypic features in FAP with APC gene mutations. Therefore, APC gene analysis seems to be a clue that can be used in an individual surveillance program. It is also suggested that genes other than the APC gene may be responsible for the development of FAP. (Acceptcd on October 16, 2001) Kawasaki Igakkaishi 27(4 ) : 279-292. 2001
