APC GENE-MUTATIONS AND EXTRAINTESTINAL PHENOTYPE OF FAMILIAL ADENOMATOUS POLYPOSIS

Background-Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q . Aims-This study assessed genotype-phenotype correlations for extrain testinal lesions in FAP. Methods-Mutations of the APC gene were compar ed with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adj usted for different ages of patients using person years of exposure. I n pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. R esults-FAP patients from the 42 families (82%) with identified mutatio ns of the APC gene had more frequent expression of extraintestinal man ifestations than affected individuals without identified mutations (ri sk ratio 1.2-4.0; significant difference for cutaneous cysts). The pre sence of a cutaneous cyst or extraintestinal cancer significantly incr eased the likelihood of detection of a mutation in the APC gene (94% a nd 92% respectively; p < 0.05). In patients without identified APC gen e mutation, linkage to the APC gene was found in one large family (lod =5.1, theta 0.01), and replication error phenotype was absent in all 2 4 neoplasms from 16 members of these nine pedigrees. Expression pigmen ted ocular fundus associated with strongly codons 541-1309, but no oth er extraintestinal manifestations were related to mutation position. M ultiplicity of extraintestinal manifestations was high with mutation i n codons 1465, 1546, and 2621. Conclusions-Patients with the colorecta l phenotype of FAP but no extraintestinal manifestations may have non- truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associa ted with pigmented ocular fundus lesions (codons 542-1309) and predisp osition to multiplicity of extraintestinal manifestations (codons 1465 , 1546, and 2621).