Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes |
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Authors: | Molenaar Jan J Koster Jan Zwijnenburg Danny A van Sluis Peter Valentijn Linda J van der Ploeg Ida Hamdi Mohamed van Nes Johan Westerman Bart A van Arkel Jennemiek Ebus Marli E Haneveld Franciska Lakeman Arjan Schild Linda Molenaar Piet Stroeken Peter van Noesel Max M Ora Ingrid Santo Evan E Caron Huib N Westerhout Ellen M Versteeg Rogier |
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Institution: | Department of Oncogenomics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. j.j.molenaar@amc.uva.nl |
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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. |
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