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, [......],
Arjan Lakeman,
Linda Schild,
Piet Molenaar,
Peter Stroeken,
Max M van Noesel,
Ingrid Ora,
Evan E Santo,
Huib N Caron,
Ellen M Westerhout,
Rogier Versteeg
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ABSTRACT: 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.
Nature 02/2012; 483(7391):589-93. · 36.28 Impact Factor
