Yamaoka Hiroaki, Ohtsu Kazuhiro, Sueda Taijiro, Yokoyama Takashi, Hiyama Eiso
Department of Surgery, Hiroshima University, Hiroshima, Japan.
Oncol Rep. 2006 Mar;15(3):551-6.
Hepatoblastoma (HBL), a major childhood malignant neoplasm, represents the most frequent malignant liver tumor in childhood. Recent reports have shown the CTNNB1 coding beta-catenin protein to be frequently mutated or deleted at hot-spot regions involving exon 3 in HBL. We investigated the genetic alterations of the CTNNB1 coding beta-catenin protein and expression of several genes downstream of Wnt signals in 4 benign and 17 malignant pediatric liver tumors (PLTs) consisting of 15 HBL, 1 hepatocellular carcinoma, and 1 hepatic immature sarcoma. Of 17 malignant PLTs, 10 (56%) revealed pathogenic alterations of the CTNNB1 gene, including 4 with missense mutations at codons 28, 32, 34 or 44, and 6 with interstitial deletions that partially or totally affected exon 3. All 6 deletions were in-frame deletions without a frame shift. The high frequency without any correlation to histological type indicates that the CTNNB1 gene alteration is a crucial event in the tumorigenesis of malignant PLTs. The immunohistochemical studies in 17 malignant PLTs demonstrated the nuclear/cytoplasmic accumulation of beta-catenin to be positive in all tumor specimens except for one hepatic sarcoma. A histological examination revealed all HBL cases involving tumors without detectable CTNNB1 gene alterations to show high expression of beta-catenin, thus indicating the accumulation of beta-catenin to be a common event in malignant PLTs, including HBL and hepatocellular carcinoma. Among the Wnt signal genes downstream of beta-catenin, E-cadherin is expressed in all malignant PLTs, while cyclin D1 expression was significantly detected in malignant PLTs with an advanced stage of disease. An immunohistological examination of nuclear accumulation of beta-catenin may thus be useful for diagnosing malignant PLTs. On the other hand, the expression of cyclin D1, a gene downstream of beta-catenin, might play a role in tumor progression.
肝母细胞瘤（HBL）是一种主要的儿童恶性肿瘤，是儿童期最常见的恶性肝肿瘤。最近的报告显示，在肝母细胞瘤中，编码β-连环蛋白的CTNNB1基因在涉及外显子3的热点区域经常发生突变或缺失。我们研究了4例良性和17例恶性儿童肝肿瘤（PLT）中CTNNB1编码β-连环蛋白的基因改变以及Wnt信号下游几个基因的表达情况，其中包括15例肝母细胞瘤、1例肝细胞癌和1例肝未成熟肉瘤。在17例恶性PLT中，10例（56%）显示CTNNB1基因存在致病性改变，包括4例密码子28、32、34或44处的错义突变，以及6例部分或完全影响外显子3的间质缺失。所有6例缺失均为框内缺失，无移码。这种高频率且与组织学类型无任何相关性表明，CTNNB1基因改变是恶性PLT肿瘤发生中的关键事件。对17例恶性PLT进行的免疫组织化学研究表明，除1例肝肉瘤外，所有肿瘤标本中β-连环蛋白的核/胞质积累均为阳性。组织学检查显示，所有未检测到CTNNB1基因改变的肝母细胞瘤病例均显示β-连环蛋白高表达，因此表明β-连环蛋白的积累是包括肝母细胞瘤和肝细胞癌在内的恶性PLT中的常见事件。在β-连环蛋白下游的Wnt信号基因中，E-钙黏蛋白在所有恶性PLT中均有表达，而细胞周期蛋白D1在疾病晚期的恶性PLT中表达明显。因此，β-连环蛋白核积累的免疫组织学检查可能有助于诊断恶性PLT。另一方面，β-连环蛋白下游基因细胞周期蛋白D1的表达可能在肿瘤进展中起作用。
