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Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

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. and van Arkel, Jennemiek, et al. (2012) In Nature 483(7391). p.107-589
Abstract
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... (More)
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. (Less)
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Nature
volume
483
issue
7391
pages
107 - 589
publisher
Nature Publishing Group
external identifiers
  • wos:000302006100037
  • scopus:84859216598
ISSN
0028-0836
DOI
10.1038/nature10910
language
English
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yes
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2f70e65f-8b95-494a-a8c4-ccf0cc68e6c5 (old id 2574912)
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2012-06-01 09:35:04
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2017-10-29 03:05:32
@article{2f70e65f-8b95-494a-a8c4-ccf0cc68e6c5,
  abstract     = {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.},
  author       = {Molenaar, Jan J. and Koster, Jan and Zwijnenburg, Danny A. and van Sluis, Peter and Valentijn, Linda J. and van der Ploeg, Ida and Hamdi, Mohamed and van Nes, Johan and Westerman, Bart A. and van Arkel, Jennemiek and Ebus, Marli E. and Haneveld, Franciska and Lakeman, Arjan and Schild, Linda and Molenaar, Piet and Stroeken, Peter and van Noesel, Max M. and Øra, Ingrid and Santo, Evan E. and Caron, Huib N. and Westerhout, Ellen M. and Versteeg, Rogier},
  issn         = {0028-0836},
  language     = {eng},
  number       = {7391},
  pages        = {107--589},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes},
  url          = {http://dx.doi.org/10.1038/nature10910},
  volume       = {483},
  year         = {2012},
}