Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes
By J. Molenaar, J. Koster, D. Zwijnenburg, P. Sluis, L. Valentijn, I. V. D. Ploeg, Mohamed Hamdi, J. Nes, B. Westerman, J. V. Arkel and 12 more. Nature, 2012
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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.
Subfields: Cancer Research, Cell Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/40bddf57b048f74eb7d7583ae83b65ea05e098b7
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In Cancer Research
Citations in the corpus
- Neuroblastoma and MYCN (2013, background): “PTPRD and ODZ3 are transmembrane receptors that localize to axons and axonal growth cones and are known to enhance neuritogenesis (Arregui et al. 2000).”
- Lessons from the cancer genome. (2013, neutral): “Termed ‘‘chromothripsis’’ (Greek, ‘‘thripsis’’ = ‘‘shattering’’), this process occurs in 2%–3% of human cancers, with an elevated prevalence in bone cancers, pediatric medulloblastoma, and neuroblastoma (Molenaar et al., 2012; Rausch et al., 2012).”
- A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations (2018, result): “This and other sequencing data support ALK as the target with the highest mutation rate among high-risk NBL patients (10, 12, 14).”