Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

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Neuroblastomais 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.


  • 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
  • Evan E. Santo
  • Huib N. Caron
  • Ellen M. Westerhout
  • Rogier Versteeg
Enheter & grupper

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Pediatrik
Sidor (från-till)589-U107
StatusPublished - 2012
Peer review utfördJa