title: Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
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.
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. j.j.molenaar@amc.uva.nl
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Danny A
authors.initials: DA
authors.lastname: Zwijnenburg
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Valentijn
authors.forename: Ida
authors.initials: I
authors.lastname: van der Ploeg
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hamdi
authors.forename: Johan
authors.initials: J
authors.lastname: van Nes
authors.forename: Bart A
authors.initials: BA
authors.lastname: Westerman
authors.forename: Jennemiek
authors.initials: J
authors.lastname: van Arkel
authors.forename: Marli E
authors.initials: ME
authors.lastname: Ebus
authors.forename: Franciska
authors.initials: F
authors.lastname: Haneveld
authors.forename: Arjan
authors.initials: A
authors.lastname: Lakeman
authors.forename: Linda
authors.initials: L
authors.lastname: Schild
authors.forename: Piet
authors.initials: P
authors.lastname: Molenaar
authors.forename: Peter
authors.initials: P
authors.lastname: Stroeken
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ora
authors.forename: Evan E
authors.initials: EE
authors.lastname: Santo
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Westerhout
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
mesh_terms: D000375:Aging / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D016000:Cluster Analysis; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D020439:Growth Cones / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D009154:Mutation; D009367:Neoplasm Staging; D016501:Neurites / Q000378:metabolism*; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D000075924:X-linked Nuclear Protein; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins