Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas
Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas
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DOI：
10.1002/ijc.26317
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发表时间：
2012-06-01
影响因子：
6.4
通讯作者：
Speleman, Frank
中科院分区：
文献类型：
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作者：
Fieuw, Annelies;Kumps, Candy;Speleman, Frank
神经母细胞瘤是一种侵袭性胚胎肿瘤，约占儿童癌症死亡人数的15%。迄今为止，尽管有关于神经母细胞瘤DNA拷贝数变化的全面基因组数据，但对驱动神经母细胞瘤发生的基因知之甚少。在这项研究中，高分辨率阵列比较基因组杂交（CGH）对188个原发性神经母细胞瘤肿瘤和33个神经母细胞瘤细胞系进行了研究，以寻找以前未检测到的复发性DNA拷贝数的增加和减少。在7例中检测到新的复发性远端染色体1q缺失(del（1)(q42.2qter)）。进一步分析可用的阵列CGH数据集发现了13个类似的远端1q缺失。在所有检测到的1q缺失中，大多数发现于无MYCN扩增的高风险11q缺失肿瘤（Fisher精确检验p = 5.61 × 10-5）。使用超高分辨率（类似于115 bp分辨率）自定义阵列覆盖11个样本的1q上的断点，在12.5 kb区域内观察到9个断点的聚类，其中8个位于7 kb拷贝数变量区域，而其余两个断点位于1.4 mb邻近区域。通常缺失的区域包含一个miRNA (hsa-mir-1537)，四个转录的超保守区元件（uc43 - uc46）和130个蛋白质编码基因，包括至少两个真正的肿瘤抑制基因，EGLN1（或PHD2）和FH。这一发现进一步有助于描述侵袭性神经母细胞瘤的基因组图谱，为鉴定导致疾病表型的基因提供了视角，并可能与评估对新分子治疗的反应有关。
Neuroblastoma is an aggressive embryonal tumor that accounts for similar to 15% of childhood cancer deaths. Hitherto, despite the availability of comprehensive genomic data on DNA copy number changes in neuroblastoma, relatively little is known about the genes driving neuroblastoma tumorigenesis. In this study, high resolution array comparative genome hybridization (CGH) was performed on 188 primary neuroblastoma tumors and 33 neuroblastoma cell lines to search for previously undetected recurrent DNA copy number gains and losses. A new recurrent distal chromosome 1q deletion (del(1)(q42.2qter)) was detected in seven cases. Further analysis of available array CGH datasets revealed 13 additional similar distal 1q deletions. The majority of all detected 1q deletions was found in high risk 11q deleted tumors without MYCN amplification (Fisher exact test p = 5.61 x 10-5). Using ultra-high resolution (similar to 115 bp resolution) custom arrays covering the breakpoints on 1q for 11 samples, clustering of nine breakpoints was observed within a 12.5-kb region, of which eight were found in a 7-kb copy number variable region, whereas the remaining two breakpoints were colocated 1.4-Mb proximal. The commonly deleted region contains one miRNA (hsa-mir-1537), four transcribed ultra conserved region elements (uc.43-uc.46) and 130 protein coding genes including at least two bona fide tumor suppressor genes, EGLN1 (or PHD2) and FH. This finding further contributes to the delineation of the genomic profile of aggressive neuroblastoma, offers perspectives for the identification of genes contributing to the disease phenotype and may be relevant in the light of assessment of response to new molecular treatments.