Preferential occurrence of chromosome breakpoints within early replicating regions in neuroblastoma
Preferential occurrence of chromosome breakpoints within early replicating regions in neuroblastoma
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DOI：
10.4161/cc.4.12.2257
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发表时间：
2005-12-01
期刊：
影响因子：
4.3
通讯作者：
Delattre, O
中科院分区：
文献类型：
--
作者：
Janoueix-Lerosey, I;Hupé, P;Delattre, O
神经母细胞瘤 ( NB ) 是一种常见的儿科颅外实体瘤，其特征是发生不平衡染色体易位，经常但不限于涉及 1 号和 17 号染色体。我们使用 1 Mb 分辨率的 BAC 阵列来进一步细化 NB 细胞系中断点的定位。使用来自在同一阵列上杂交的 G(1) 和 S 期流式分选细胞核的 DNA，在 7 个 NB 细胞系中评估了复制时间曲线。引人注目的是，不同 NB 细胞系之间的复制时间分布非常相似。此外，在 NB 细胞系和类淋巴母细胞之间也观察到显着水平的相似性。使用自适应权重平滑过程进行分段分析以确定坐标复制区域。超过50%的断点映射到早期复制区域，占整个基因组的23.7%。因此，早期复制区域每 108 个碱基的断点频率为 10.84，而晚期复制区域仅为 2.94，这些差异非常显着 (p < 10(-4))。当 NB 中两个最常见的易位伴侣 1 号和 17 号染色体被排除在统计分析之外时，也观察到了这种强相关性。这些结果明确地建立了不平衡易位之间的联系，其最可能的发生机制依赖于断裂诱导的复制和基因组的早期复制。
Neuroblastoma ( NB) is a frequent paediatric extra cranial solid tumor characterized by the occurrence of unbalanced chromosome translocations, frequently, but not exclusively, involving chromosomes 1 and 17. We have used a 1 Mb resolution BAC array to further refine the mapping of breakpoints in NB cell lines. Replication timing profiles were evaluated in 7 NB cell lines, using DNAs from G(1) and S phases flow sorted nuclei hybridised on the same array. Strikingly, these replication timing profiles were highly similar between the different NB cell lines. Furthermore, a significant level of similarity was also observed between NB cell lines and lymphoblastoid cells. A segmentation analysis using the Adaptative Weights Smoothing procedure was performed to determine regions of coordinate replication. More than 50% of the breakpoints mapped to early replicating regions, which account for 23.7% of the total genome. The breakpoints frequency per 108 bases was therefore 10.84 for early replicating regions, whereas it was only 2.94 for late replicating regions, these difference being highly significant ( p < 10(-4)). This strong association was also observed when chromosomes 1 and 17, the two most frequent translocation partners in NB were excluded from the statistical analysis. These results unambiguously establish a link between unbalanced translocations, whose most likely mechanism of occurrence relies on break-induced replication, and early replication of the genome.