Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes
Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes
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DOI：
10.1002/mc.20412
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发表时间：
2008-09-01
影响因子：
4.6
通讯作者：
Kaneko, Yasuhiko
中科院分区：
文献类型：
--
作者：
Haruta, Masayuki;Matsumoto, Yoshiyuki;Kaneko, Yasuhiko
BUB1B和RASSF1A基因在有丝分裂检查点中发挥着特殊的作用，它们的缺陷可能会导致小鼠成纤维细胞和人类癌细胞的染色体不稳定或非整倍体，但很少有研究报道这些基因的缺陷与人类肿瘤标本中染色体变化的相关性。我们用中期比较基因组杂交技术检测了25例肾母细胞瘤的染色体异常，并将其分为14例超二倍体(50-gt；=染色体)、2例近或假二倍体和9例二倍体肿瘤。我们还研究了BUB1B和RASSF1A的各个分子方面，并评估了染色体变化与这两个基因状态之间的关系。未发现肿瘤发生BUB1B突变。BubR1蛋白(BUB1B基因产物)在6个超二倍体、近二倍体或假二倍体肿瘤中有5个未检测到或表达降低，而在5个二倍体肿瘤中有4个表达增加，而所有7个肿瘤均显示BUB1B基因表达，与其染色体类型无关。此外，在16例超二倍体或近或假二倍体肿瘤中有13例发现RASSF1A完全甲基化，而在9例二倍体肿瘤中有5例发现RASSF1A未甲基化。3例超二倍体、近二倍体或假二倍体肿瘤和4例二倍体肿瘤中发现部分RASSF1A甲基化。因此，在大多数超二倍体或接近或假二倍体肿瘤中，BubR1蛋白表达降低，RASSF1A启动子区域完全甲基化，而在大多数二倍体肿瘤中，BubR1蛋白表达增加，RASSF1A未甲基化。这些发现提示，联合使用的BubR1蛋白下调和RASSF1A高甲基化可能与肾母细胞瘤染色体改变的形成有关。(C)2008年Wiley-Liss，Inc.
BUB1B and RASSF1A genes play specific roles in the mitotic checkpoint, and their defects may cause chromosome instability or aneuploidy in mouse fibroblasts and human cancer cell lines, however, few studies have reported a correlation between defects in these genes and chromosome changes in human tumor samples. We examined chromosome abnormalities in 25 Wilms tumors by metaphase comparative genomic hybridization, and classified them into 14 hyperdiploid (50 >= chromosomes), 2 near-or-pseudodiploid, and 9 diploid tumors. We also examined various molecular aspects of BUB1B and RASSF1A, and evaluated the relationship between chromosome changes and the status of both genes. No tumors showed BUB1B mutation. BubR1 protein (BUB1B gene product) expression was undetectable or decreased in five of six hyperdiploid or near-or-pseudodiploid tumors and increased in four of five diploid tumors, whereas all seven tumors examined showed BUB1B mRNA expression irrespective of their chromosome pattern. Furthermore, while complete promoter methylation of RASSF1A was found in 13 of 16 hyperdiploid or near-or-pseudodiploid tumors, unmethylated RASSF1A was found in 5 of 9 diploid tumors. Partial RASSF1A methylation was found in three hyperdiploid or near-or-pseudodiploid tumors and in four diploid tumors. Thus, BubR1 protein expression decreased, and the promoter region of RASSF1A was completely methylated in the great majority of hyperdiploid or near-or-pseudodiploid tumors, BubR1 protein expression increased and RASSF1A was unmethylated in the majority of diploid tumors. These findings suggest that the combined BubR1 protein down-regulation and RASSF1A hypermethylation might be implicated in the formation of chromosomal changes found in Wilms tumors. (C) 2008 Wiley-Liss, Inc.