Łastowska Maria, Chung Yeun-Jun, Cheng Ching Ngan, Haber Michelle, Norris Murray D, Kees Ursula R, Pearson Andrew D J, Jackson Michael S
Institute of Human Genetics, International Centre for Life, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
Genes Chromosomes Cancer. 2004 Jun;40(2):158-63. doi: 10.1002/gcc.20031.
Gain of chromosome arm 17q is the most frequent chromosomal change in human neuroblastoma and is a powerful predictor of adverse outcome of disease. This suggests that the region of gain includes a gene or genes critical for tumor pathogenesis. Analyses of breakpoint positions have revealed that the shortest region of gain (SRG) extends from MPO (17q23.1) to 17qter. Because this encompasses >300 genes, it precludes the identification of candidate genes from human breakpoint data alone. However, mouse chromosome 11, which is syntenic to human chromosome 17, is gained in up to 30% of neuroblastoma tumors developed in a murine MYCN transgenic model of this disease. To confirm that this key genetic change indicates the involvement of a molecular pathway conserved between mouse and man and is not occurring coincidentally in the transgenic model, we used fluorescence in situ hybridization to analyze sporadic cases of both mouse and rat neuroblastoma. Our results confirmed the presence of chromosome 11 gain in all three of the mouse cell lines we analyzed, with the SRG extending from Stat5b (101.6 Mb) to tel. In addition, the rat neuroblastoma cell line harbors an extra copy of distal chromosome 10, extending from 92.8 to 109.3 Mb, which is also syntenic to human 17q. Comparison of the regions gained in all three species has excluded 4.2 Mb from the previously defined region of 17q gain in humans as a likely location of the candidate gene or genes, and strongly suggests that the molecular etiology of neuroblastoma is similar in all three species.
17号染色体长臂扩增是人类神经母细胞瘤中最常见的染色体改变，也是疾病不良预后的有力预测指标。这表明扩增区域包含一个或多个对肿瘤发病机制至关重要的基因。对断点位置的分析表明，最短扩增区域（SRG）从MPO（17q23.1）延伸至17q末端。由于这包含了300多个基因，仅从人类断点数据中无法确定候选基因。然而，在这种疾病的小鼠MYCN转基因模型中，高达30%的神经母细胞瘤肿瘤出现了与人类17号染色体同线性的小鼠11号染色体扩增。为了证实这一关键基因改变表明小鼠和人类之间存在保守的分子途径参与其中，而非在转基因模型中偶然发生，我们使用荧光原位杂交技术分析了小鼠和大鼠神经母细胞瘤的散发病例。我们的结果证实，在我们分析的所有三个小鼠细胞系中都存在11号染色体扩增，SRG从Stat5b（101.6 Mb）延伸至末端。此外，大鼠神经母细胞瘤细胞系含有一条额外的远端10号染色体拷贝，从92.8 Mb延伸至109.3 Mb，这也与人类17q同线性。对所有三个物种中扩增区域的比较排除了人类先前定义的17q扩增区域中4.2 Mb作为候选基因可能位置的可能性，并强烈表明神经母细胞瘤的分子病因在所有三个物种中相似。
