APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis

Correlations between germline APG mutation sites and colorectal pathophenot ypes, as evaluated by the direct count of adenomas at colectomy, were inves tigated analysing colectomy specimens from 29 FAP patients carrying one mis -sense (codon 208) and 14 frame-shift or non-sense APC mutations (codons 23 2, 367, 437, 623; 876,995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The missense mutation at codon 208 was associated with a relatively mild c olorectal pathophenotype. The mutation at codon 367,subject to alternative splicing; was associated with attenuated FAP. The mutation at codon 1309 wa s associated with the profuse colorectal adenomatosis. For 13 mutations, pr edicted to result in null alleles or truncated APC proteins, we correlated density and distribution of colorectal adenomas with the predicted function al effects of the mutation. The most severe colorectal pathophenotype was s ignificantly associated with the truncating mutation at codon 1309, which i s located downstream to the I beta-catenin binding-domain but upstream II b eta-catenin-binding domain. Mutations between codons 867 and 1114, which af fect the I beta-catenin binding domain, as well as mutations occurring in e xons 6 and 9, predicted to result in null alleles, were associated with a l ess severe colorectal pathophenotype. Overall, the highest number of adenom as was detected in the right colon, followed by the left colon, transverse colon sigma and rectum. However, the highest density of adenomas was observ ed in the left colon, followed by the right colon, sigma, transverse colon and rectum. Colorectal carcinomas, observed in only five patients, were all in the left colon. (C) 2000 Cancer Research Campaign.