Janoueix-Lerosey Isabelle, Hupé Philippe, Maciorowski Zofia, La Rosa Philippe, Schleiermacher Gudrun, Pierron Gaëlle, Liva Stéphane, Barillot Emmanuel, Delattre Olivier
Laboratoire de Pathologie Moléculaire des Cancers, Institut Curie, Paris, France.
Cell Cycle. 2005 Dec;4(12):1842-6. doi: 10.4161/cc.4.12.2257. Epub 2005 Dec 14.
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 G1 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 10(8) 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.
神经母细胞瘤（NB）是一种常见的儿科颅外实体瘤，其特征是出现染色体不平衡易位，这种易位经常（但并非仅仅）涉及1号和17号染色体。我们使用了分辨率为1 Mb的BAC阵列来进一步精确绘制NB细胞系中断点的图谱。使用来自G1期和S期流式分选细胞核的DNA在同一阵列上杂交，对7个NB细胞系的复制时间图谱进行了评估。令人惊讶的是，不同NB细胞系之间的这些复制时间图谱高度相似。此外，在NB细胞系和淋巴母细胞之间也观察到了显著的相似程度。使用自适应权重平滑程序进行了分段分析，以确定协同复制区域。超过50%的断点映射到早期复制区域，这些区域占基因组总量的23.7%。因此，早期复制区域每10^8个碱基的断点频率为10.84，而晚期复制区域仅为2.94，这些差异具有高度显著性（p < 10^-4）。当在统计分析中排除NB中两个最常见的易位伙伴1号和17号染色体时，也观察到了这种强烈的关联。这些结果明确地建立了不平衡易位（其最可能的发生机制依赖于断裂诱导复制）与基因组早期复制之间的联系。
