Jeng Y M, Wu M Z, Mao T L, Chang M H, Hsu H C
Department of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
Cancer Lett. 2000 Apr 28;152(1):45-51. doi: 10.1016/s0304-3835(99)00433-4.
Hepatoblastoma (HB) is the most common malignant hepatic tumor during early childhood. Its molecular pathogenesis is still poorly understood. Mutations of adenomatous polyposis coli (APC) gene have been identified in sporadic cases and in individuals associated with familial adenomatous polyposis syndrome. beta-catenin is a key element in the cadherin-mediated cell adhesion system and Wnt/wingless pathway, and is controlled by APC. APC affects the degradation of beta-catenin by its NH(2)-terminal phosphorylation on the serine/threonine residues of exon 3. Mutations of these phosphorylation sites are primary targets for activating mutations in several types of human cancer and lead to nuclear accumulation of beta-catenin protein. In this study, we examined nine patients with HB using immunohistochemistry and direct DNA sequencing. All nine cases showed predominant nuclear expression of beta-catenin. Eight cases (89%) showed mutations involving exon 3 of the beta-catenin gene, including five with deletions and three with missense mutations. All five deletions were in-frame deletions without frameshift. The very high frequency of mutations in the beta-catenin gene suggests that beta-catenin mutations are crucial in the tumorigenesis of HB.
肝母细胞瘤（HB）是儿童早期最常见的肝脏恶性肿瘤。其分子发病机制仍知之甚少。在散发性病例以及与家族性腺瘤性息肉病综合征相关的个体中已发现腺瘤性息肉病 coli（APC）基因突变。β-连环蛋白是钙黏蛋白介导的细胞黏附系统和Wnt/无翅通路中的关键元件，并受APC调控。APC通过其在第3外显子丝氨酸/苏氨酸残基上的NH(2)-末端磷酸化来影响β-连环蛋白的降解。这些磷酸化位点的突变是几种人类癌症激活突变的主要靶点，并导致β-连环蛋白蛋白在细胞核内积累。在本研究中，我们使用免疫组织化学和直接DNA测序对9例HB患者进行了检查。所有9例病例均显示β-连环蛋白主要在细胞核中表达。8例（89%）显示涉及β-连环蛋白基因第3外显子的突变，其中5例为缺失突变，3例为错义突变。所有5例缺失均为框内缺失，无移码。β-连环蛋白基因的高突变频率表明β-连环蛋白突变在HB的肿瘤发生中至关重要。
