Large-scale N-terminal deletions but not point mutations stabilize β-catenin in small bowel carcinomas, suggesting divergent molecular pathways of small and large intestinal carcinogenesis
Large-scale N-terminal deletions but not point mutations stabilize β-catenin in small bowel carcinomas, suggesting divergent molecular pathways of small and large intestinal carcinogenesis
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DOI：
10.1002/path.2362
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发表时间：
2008-07-01
影响因子：
7.3
通讯作者：
Blaeker, H.
中科院分区：
文献类型：
--
作者：
Breuhahn, K.;Singh, S.;Blaeker, H.
小肠腺癌罕见，其分子发病机制尚不完全清楚。β -连环蛋白是wnt/无翅信号的一种介质，在50%的散发性癌中可以检测到β -连环蛋白的稳定，但与结直肠癌相比，这一发现不能用大肠腺瘤性息肉病（APC）的失活来解释。为了阐明β -catenin稳定在小肠腺癌中的分子背景，我们研究了20例非家族性腺瘤性大肠息肉病（FAP）相关肿瘤，包括5例微卫星不稳定癌，通过免疫组织化学、western blot分析和RNA和DNA水平的序列分析，研究了β -catenin改变。在50%的癌中发现β -连环蛋白的核积聚。在30%的肿瘤中，核稳定仅限于侵袭前沿的肿瘤细胞，而20%的肿瘤在所有区域均表现出强烈的均匀核稳定。β -连环蛋白基因（CTNNB1）的大量缺失和插入导致rna转录水平上外显子3和4的部分或完全帧内缺失，仅在微卫星稳定癌中发现。突变导致异常β -连环蛋白稳定，缺少大部分n端蛋白结构域。CTNNB1未见点突变。我们的数据表明，大的基因内CTNNB1突变稳定了小肠腺癌中的β -连环蛋白，并影响了该蛋白的亚细胞分布。与结肠癌相比，APC和CTNNB1点突变似乎在癌变中都没有发挥重要作用，这表明wnt/无翅控制在小肠和大肠中的机制存在差异。版权所有2008年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Small intestinal adenocarcinoma is rare and its molecular pathogenesis is incompletely understood. Stabilization of beta-catenin, a mediator of wnt/wingless signalling, can be detected in 50% of sporadic carcinomas but, in contrast to colorectal cancer, this finding can not be explained by the inactivation of adenomatous polyposis coli (APC). In order to elucidate the molecular background of beta-catenin stabilization in small intestinal adenocarcinoma, we investigated 20 non-familial adenomatous polyposis coli (FAP)-associated tumours, including five microsatellite-unstable carcinomas for beta-catenin alterations, by immunohistochemistry, western blot analysis and sequence analysis on the RNA and DNA levels. Nuclear accumulation of beta-catenin was found in 50% of carcinomas. In 30%, nuclear stabilization was restricted to tumour cells at the invasion front, while 20% of tumours displayed intense homogeneous nuclear stabilization throughout all areas. Large deletions and insertions in the beta-catenin gene (CTNNB1) resulting in a partial or complete in-frame loss of exons 3 and 4 on the RNA-transcript level were found in the latter, exclusively microsatellite-stable carcinomas. The mutations resulted in the stabilization of aberrant beta-catenin lacking large parts of N-terminal protein domains. No point mutations in CTNNB1 were observed. Our data show that large intragenic CTNNB1 mutations stabilize beta-catenin in small intestinal adenocarcinomas and influence the subcellular distribution of the protein. In contrast to colon carcinomas, neither APC nor CTNNB1 point mutations seem to play a significant role in carcinogenesis, indicating divergent mechanisms of wnt/wingless control in the small and the large intestine. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.