Phenotype-genotype correlations in an extended family with adenomatosis coli and an unusual APC gene mutation

PURPOSE: Genotype-phenotype correlations in familial adenomatous polyposis are only partially understood and, in particular, little is known about the biomolecular characteristics of desmoid tumors, which are one of the most serious and frequent manifestations of familial adenomatous polyposis. In t he present study, we describe a family with familial adenomatous polyposis, with peculiar clinical characteristics (i.e., frequency and severity of de smoid neoplasms) associated with an unusual mutation of the adenomatosis po lyposis coli gene. If confirmed by other investigations, these findings mig ht help to understand the biologic mechanisms by which specific adenomatosi s polyposis coli mutations predispose to desmoid tumors. METHODS: The famil y with familial adenomatous polyposis, living in southern Italy, was studie d from 1985 to the end of 1999; at this date, 15 individuals have been affe cted by histologically verified familial adenomatous polyposis, 11 of whom had desmoid tumors, A total of 19 family members were studied for adenomato sis polyposis coli gene mutations; 13 of them tested positive and 6 negativ e. The analytical procedure-previously described-consisted of the extractio n of peripheral blood cell DNA, amplification of exon 15 by polymerase chai n reaction, single-strand conformation polymorphism analysis, and direct se quencing of the DNA fragment containing the mutation. RESULTS: The main cli nical features of the family were 1) a high frequency of desmoid tumors and , consequently, a high penetrance of the desmoid trait in all branches of t he family and in 11 (73.3 percent) of 15 affected individuals and 2) severi ty of desmoids in at least 4 family members, 2 of whom died for causes rela ted to the presence of these tumors. The molecular basis of the disease was an uncommon mutation of the adenomatosis polyposis coli gene, consisting o f a large deletion of 310 base pairs at codon 1,464, with duplication of th e breakpoint (4,394ins15del310), leading to a stop codon at position 1,575. CONCLUSIONS: The present study shows that a truncating mutation in the ade nomatosis polyposis coli gene at the beginning of the region frequently ass ociated with desmoids induced a familial adenomatous polyposis phenotype fe atured by a high penetrance of the desmoid trait, with severe disease in se veral affected members of both sexes. The study may help to understand the biologic mechanisms of genotype-phenotype correlations in adenomatosis coli .