APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis

Abstract

Correlations between germline APC mutation sites and colorectal pathophenotypes, as evaluated by the direct count of adenomas at colectomy, were investigated analysing colectomy specimens from 29 FAP patients carrying one mis-sense (codon 208) and 14 frame-shift or non-sense APC mutations (codons 232, 367, 437, 623, 876, 995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The mis-sense mutation at codon 208 was associated with a relatively mild colorectal pathophenotype. The mutation at codon 367, subject to alternative splicing, was associated with attenuated FAP. The mutation at codon 1309 was associated with the profuse colorectal adenomatosis. For 13 mutations, predicted to result in null alleles or truncated APC proteins, we correlated density and distribution of colorectal adenomas with the predicted functional effects of the mutation. The most severe colorectal pathophenotype was significantly associated with the truncating mutation at codon 1309, which is located downstream to the I β-catenin binding domain but upstream II β-catenin-binding domain. Mutations between codons 867 and 1114, which affect the I β-catenin binding domain, as well as mutations occurring in exons 6 and 9, predicted to result in null alleles, were associated with a less severe colorectal pathophenotype. Overall, the highest number of adenomas was detected in the right colon, followed by the left colon, transverse colon sigma and rectum. However, the highest density of adenomas was observed 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. © 2000 Cancer Research Campaign

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

“…38. This finding corresponds with the published correlation between the presence of a germline mutation in the mutation cluster region (MCR) and the severity of polyposis (Ficari et al, 2000). It appears that the germline mutation in the MCR (codons 1250 -1500) could contribute to the occurrence of somatic MCR mutations and increase the likelihood of polyposis (Lamlum et al, 1999).…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Somatic APC mutations, which lead to an aberrant concentration of b-catenin, as shown in, for example, colon carcinomas (Ficari et al, 2000), have seldom been described in HCCs. Instead, nuclear accumulation is in part explained by stabilizing point mutations and deletions in the N-terminal phosphorylation domain of b-catenin, which is observed in 19-44% of all cases (de La Coste et al, 1998;Miyoshi et al, 1998;Cui et al, 2003;Prange et al, 2003;Fujito et al, 2004).…”

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

“…APC mutations were compiled from Dobbie et al [1996], van der Luijt et al [1997], Armstrong et al [1997], Giarola et al [1999], Won et al [1999], Wallis et al [1999], Gebert et al [1999], Ponz de Leon et al [1999], Fidalgo et al [1999], Ficari et al [2000], Cao et al [2000], and Friedl et al [2001]. Major events, often overlooked in screenings [e.g., Wallis et al, 1999], are responsible for B10% of all cases of FAP [Su et al, 2000;Flintoff et al, 2001].…”