Sequence variants of the Axin gene in hepatoblastoma
Sequence variants of the Axin gene in hepatoblastoma
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DOI：
10.1016/s1386-6346(02)00264-4
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发表时间：
2003-02-01
影响因子：
4.2
通讯作者：
Okada, A
中科院分区：
文献类型：
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作者：
Miao, JY;Kusafuka, T;Okada, A
Writ 信号通路在胚胎发育和肿瘤发生中起着关键作用。作为令状信号转导的一部分，轴蛋白复合物的功能受到抑制，导致β-连环蛋白的积累。在肝母细胞瘤中，已证明 APC（腺瘤性结肠息肉病）功能丧失或 β-连环蛋白激活，这是参与 Writ 信号传导的另外两个成分。由于肝母细胞瘤显示 β-连环蛋白免疫组织化学阳性的频率高于其突变频率，因此我们分析了 Axin 基因作为导致肝母细胞瘤中 β-连环蛋白积累的候选基因。使用24组引物在22个肝母细胞瘤和一些配对的正常组织中通过PCR-SSCP检查了Axin基因的编码区。对显示异常条带模式的样品进行直接测序分析。我们总共鉴定了八个外显子变异和四个内含子核苷酸取代。外显子中的 7 个变异是沉默突变，然而，在一个肝母细胞瘤中发现的密码子 95 处的剩余变异 (ACG --> ATG) 预计会导致氨基酸从苏氨酸变为蛋氨酸。该患者的配对外周血DNA也显示出同样的变化；我们认为这是Axin基因的种系突变。我们的结果表明，Axin 基因的突变可能在儿童肝母细胞瘤的一部分中具有致瘤功能。 (C) 2002 Elsevier Science B.V. 保留所有权利。
The Writ signaling pathway plays critical roles in the embryonic development and tumorigenesis. As a part of the Writ signal transduction, the function of Axin complex is inhibited, leading to accumulation of beta-catenin. In hepatoblastomas, loss of APC (adenomatous polyposis coli) function or activation of beta-catenin that are the other two components involving in Writ signaling has been demonstrated. Because hepatoblastoma shows immunohistochemical positivity of beta-catenin more often than its mutation frequency, we analyzed the Axin gene as a candidate to lead beta-catenin accumulation in hepatoblastoma. The coding region of the Axin gene was examined by PCR-SSCP using 24 sets of the primers in 22 hepatoblastomas and some paired normal tissues. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. We identified totally eight variants in the exons and four intronic nucleotide substitutions. Seven variants in the exons were silent mutations, however, the remaining variant at codon 95 (ACG --> ATG) found in one hepatoblastoma predicted to result in an amino acid change from threonine to methionine. The paired peripheral blood DNAs from this patient also showed the same change; we suggested that it was a germline mutation of Axin gene. Our results suggest that mutation of the Axin gene may have a tumorigenic function in a subset of childhood hepatoblastomas. (C) 2002 Elsevier Science B.V. All rights reserved.