Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Jan J. Molenaar, Jan Koster, Danny A. Zwijnenburg, Peter Van Sluis, Linda J. Valentijn, Ida Van Der Ploeg, Mohamed Hamdi, Johan Van Nes, Bart A. Westerman, Jennemiek Van Arkel, Marli E. Ebus, Franciska Haneveld, Arjan Lakeman, Linda Schild, Piet Molenaar, Peter Stroeken, Max M. Van Noesel, Ingrid Øra, Evan E. Santo, Huib N. CaronEllen M. Westerhout, Rogier Versteeg, Ingrid Ora

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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. 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.

Original languageEnglish
Pages (from-to)589-593
Number of pages5
Issue number7391
Publication statusPublished - 29 Mar 2012

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