Ficari F, Cama A, Valanzano R, Curia M C, Palmirotta R, Aceto G, Esposito D L, Crognale S, Lombardi A, Messerini L, Mariani-Costantini R, Tonelli F, Battista P
Department of Clinical Physiopathology, University of Florence, Italy.
Br J Cancer. 2000 Jan;82(2):348-53. doi: 10.1054/bjoc.1999.0925.
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 beta-catenin binding domain but upstream II beta-catenin-binding domain. Mutations between codons 867 and 1114, which affect the I beta-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.
通过在结肠切除术中直接计数腺瘤来评估种系APC突变位点与结直肠病理表型之间的相关性，对29例携带一个错义突变（密码子208）以及14例移码或无义APC突变（密码子232、367、437、623、876、995、1061、1068、1075、1112、1114、1309、1324、1556）的家族性腺瘤性息肉病（FAP）患者的结肠切除标本进行了分析。密码子208处的错义突变与相对较轻的结直肠病理表型相关。密码子367处的突变存在可变剪接，与减弱的FAP相关。密码子1309处的突变与大量结直肠腺瘤病相关。对于预计会导致无效等位基因或截短的APC蛋白的13种突变，我们将结直肠腺瘤的密度和分布与突变的预测功能效应进行了关联。最严重的结直肠病理表型与密码子1309处的截短突变显著相关，该突变位于β-连环蛋白结合结构域I的下游但β-连环蛋白结合结构域II的上游。影响β-连环蛋白结合结构域I的密码子867至1114之间的突变，以及预计会导致无效等位基因的外显子6和9中的突变，与不太严重的结直肠病理表型相关。总体而言，腺瘤数量最多的是在右半结肠，其次是左半结肠、横结肠、乙状结肠和直肠。然而，腺瘤密度最高的是在左半结肠，其次是右半结肠、乙状结肠、横结肠和直肠。仅在5例患者中观察到结直肠癌，均位于左半结肠。
