Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

摘要

在这项研究中，全基因组测序方法被人用来在87个成神经细胞瘤（一种儿童时期所患的交感神经系统肿瘤）患者中识别基因缺陷。分析显示，很少有重现性的、使氨基酸发生改变的突变，但在神经突生成长“神经生长锥”的延伸中中挥功能的一系列基因在侵袭性晚期肿瘤中被删除。“染色体碎裂”（染色体的局部破碎）是晚期肿瘤中的普遍现象，一般都与不良预后相关。%Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.