Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
Molenaar, Jan J. 1*; Koster, Jan 1*; Zwijnenburg, Danny A. 1; van Sluis, Peter 1; Valentijn, Linda J. 1; van der Ploeg, Ida 1; Hamdi, Mohamed 1; van Nes, Johan 1; Westerman, Bart A. 1; van Arkel, Jennemiek 1; Ebus, Marli E. 1; Haneveld, Franciska 1; Lakeman, Arjan 1; Schild, Linda 1; Molenaar, Piet 1; Stroeken, Peter 1; van Noesel, Max M. 2; Ora, Ingrid 1,3; Santo, Evan E. 1; Caron, Huib N. 4; Westerhout, Ellen M. 1; Versteeg, Rogier 1
[Letter] Nature. 483(7391):589-593, March 29, 2012.

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: 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 tumour 1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%) 2-5. 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 6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization 7-9. 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.

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