Clinical features and genotype-phenotype correlations in 41 Italian families with Adenomatosis Coli

Background: Familial Adenomatous Polyposis in an autosomal dominant disease in which the large bowel is carpeted by polyps of various dimensions appea ring during the second or third decade of life. Several extracolonic manife stations complete the clinical spectrum of Familial Adenomatous Polyposis. If untreated, the disease lends invariably to colorectal cancel: The gene r esponsible for the disease, adenomatous Polyposis Coli, has been localized at chromosome 5q21. Aims: To describe the clinical features of 156 Familial Adenomatous Polypos is patients (from 41 families) and to analyze possible correlations between genotype and phenotype. Patients and Methods: Familial Adenomatous Polyposis was defined as the pre sence of 100 or more polyps in the large bowel. In 17 families (41 %), the proband was the only affected individual (single cases). Adenomatous Polypo sis Coli gene mutations were studied on DNA extracted from peripheral white blood cells and evaluated by polymerase chain reaction single strand confo rmation polymorphism, followed by direct sequencing of samples showing abno rmal banding at single strand conformation polymorphism. Results: The large majority of Familial Adenomatous Polyposis patients unde rwent surgery; colectomy with ileorectal anastomosis was the most frequent approach, however cancer of the rectal stump developed in 11.6% of patients submitted to colectomy and ileorectal anastomosis. Adenomas were rare in t he stomach (8.8%), but their frequency increased in the duodenum (33.8%) an d jejunum (55.0%, chi(2) for trend 23.7, p<0.001). Desmoid rumours were dia gnosed in 17 patients (10.9% of the total) and in 6 families. Mutations of the Adenomatous Polyposis Coli gene were studied in 20 out of 25 families ( 80%) and on a total of 75 individuals. The most frequent alterations were I to 5 bp deletions lending to stop codons and truncated proteins. Desmoid tu mors, presence of duodenal or jejunal adenomas were associated with an ampl e range of mutations, from codon 215 to codon 1464, In contrast, particular ly severe polyposis (mean age at appearance of polyps 11-16 years, and of c ancer development 27-32 years) was associated with a "hot-spot" mutation si te at codons 1303-1309. Conclusions: In patients with Familial Adenomatous Polyposis, subtotal cole ctomy with ileorectal anastomosis is still the treatment of choice. Adenoma tous lesions seem to show a "gradient" distribution from the stomach to the large bowel. Desmoid tumours are relatively common, though their incidence is limited to some of the families. Constitutional mutations can be detect ed in 80% of the investigated families. Genotype-phenotype correlations sho wed a hat-spot at codons 1303-1309, frequently associated with severe polyp osis.