PHENOTYPIC-EXPRESSION OF DISEASE IN FAMILIES THAT HAVE MUTATIONS IN THE 5'-REGION OF THE ADENOMATOUS POLYPOSIS-COLI GENE

Background: Germline mutation in a gene on chromosome 5 (the adenomato us polyposis coli gene) causes familial adenomatous polyposis of the c olorectum. Phenotypic manifestations of this condition vary, but the e xact relation of the phenotype to the mutation site along the gene has not been fully described. Objective: To determine how the location of mutations along a gene that is associated with multiple colorectal po lyps (the adenomatous polyposis coli gene) is related to the phenotypi c expression of the syndrome in families. Design: Prospective cohort s tudy. Setting: Polyposis registry. Patients: 20 patients from 7 famili es that had mutations in the adenomatous polyposis coli gene that were located toward the 5' end of codon 158 (proximal 5' families), were c ompared with 52 patients from 7 families that had mutations downstream from codon 158, in codons 179 to 625 (distal 5' families). Measuremen ts: Sex, age at diagnosis of familial adenomatous polyposis, number of polyps at first examination of the colon, distribution of polyps, age at diagnosis of colorectal cancer, and location of colorectal cancer. Results: Mutations that were proximal to codon 158 were found in 7 of 112 families (6%). At the first examination of the colon, 8 of 17 (47 %) patients in proximal 5' families and 9 of 48 (19%) patients of simi lar ages in distal 5' families were found to have fewer than 100 adeno mas (P = 0.029). The distribution of polyps was frequently right-sided in patients in proximal 5' families (P = 0.001). The cumulative proba bility of survival without colorectal cancer was greater for patients in proximal 5' families (P = 0.041). Conclusions: Families with adenom atous polyposis that have proximal 5' mutations of the adenomatous pol yposis coli gene are more likely to have a heterogeneous phenotype wit h delayed development of colonic polyposis and colorectal cancer than are families with distal 5' mutations of the gene. Management should i nclude genotyping of patients who are at risk, colonoscopic surveillan ce of genotypically positive persons, and prophylactic colectomy if se veral adenomas are found.