Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

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; Marli E Ebus; Franciska Haneveld; 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

doi:10.1038/nature10910

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

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, Marli E Ebus, Franciska Haneveld, Arjan Lakeman, Linda Schild, Piet Molenaar, Peter Stroeken, Max M van Noesel, Ingrid Ora, Evan E Santo, Huib N CaronEllen M Westerhout, Rogier Versteeg^*

^*Corresponding author for this work

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Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	589-93
Number of pages	5
Journal	Nature
Volume	483
Issue number	7391
DOIs	https://doi.org/10.1038/nature10910
Publication status	Published - 22 Feb 2012
Externally published	Yes

Keywords

Aging/genetics
Chromosomes, Human/genetics
Cluster Analysis
DNA Helicases/genetics
DNA Mutational Analysis
Gene Expression Regulation, Neoplastic
Genome, Human/genetics
Growth Cones/metabolism
Guanine Nucleotide Exchange Factors/genetics
Humans
Mutation
Neoplasm Staging
Neurites/metabolism
Neuroblastoma/diagnosis
Nuclear Proteins/genetics
Prognosis
T-Lymphoma Invasion and Metastasis-inducing Protein 1
X-linked Nuclear Protein
rac GTP-Binding Proteins/metabolism
rho GTP-Binding Proteins/metabolism

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Molenaar, J. J., Koster, J., Zwijnenburg, D. A., van Sluis, P., Valentijn, L. J., van der Ploeg, I., Hamdi, M., van Nes, J., Westerman, B. A., van Arkel, J., Ebus, M. E., Haneveld, F., Lakeman, A., Schild, L., Molenaar, P., Stroeken, P., van Noesel, M. M., Ora, I., Santo, E. E., ... Versteeg, R. (2012). Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature, 483(7391), 589-93. https://doi.org/10.1038/nature10910

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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.",

keywords = "Aging/genetics, Chromosomes, Human/genetics, Cluster Analysis, DNA Helicases/genetics, DNA Mutational Analysis, Gene Expression Regulation, Neoplastic, Genome, Human/genetics, Growth Cones/metabolism, Guanine Nucleotide Exchange Factors/genetics, Humans, Mutation, Neoplasm Staging, Neurites/metabolism, Neuroblastoma/diagnosis, Nuclear Proteins/genetics, Prognosis, T-Lymphoma Invasion and Metastasis-inducing Protein 1, X-linked Nuclear Protein, rac GTP-Binding Proteins/metabolism, rho GTP-Binding Proteins/metabolism",

author = "Molenaar, \{Jan J\} and Jan Koster and Zwijnenburg, \{Danny A\} and \{van Sluis\}, Peter and Valentijn, \{Linda J\} and \{van der Ploeg\}, Ida and Mohamed Hamdi and \{van Nes\}, Johan and Westerman, \{Bart A\} and \{van Arkel\}, Jennemiek and Ebus, \{Marli E\} and Franciska Haneveld and Arjan Lakeman and Linda Schild and Piet Molenaar and Peter Stroeken and \{van Noesel\}, \{Max M\} and Ingrid Ora and Santo, \{Evan E\} and Caron, \{Huib N\} and Westerhout, \{Ellen M\} and Rogier Versteeg",

year = "2012",

month = feb,

day = "22",

doi = "10.1038/nature10910",

language = "English",

volume = "483",

pages = "589--93",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

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Molenaar, JJ, Koster, J, Zwijnenburg, DA, van Sluis, P, Valentijn, LJ, van der Ploeg, I, Hamdi, M, van Nes, J, Westerman, BA, van Arkel, J, Ebus, ME, Haneveld, F, Lakeman, A, Schild, L, Molenaar, P, Stroeken, P, van Noesel, MM, Ora, I, Santo, EE, Caron, HN, Westerhout, EM & Versteeg, R 2012, 'Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes', Nature, vol. 483, no. 7391, pp. 589-93. https://doi.org/10.1038/nature10910

TY - JOUR

T1 - Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

AU - Molenaar, Jan J

AU - Koster, Jan

AU - Zwijnenburg, Danny A

AU - van Sluis, Peter

AU - Valentijn, Linda J

AU - van der Ploeg, Ida

AU - Hamdi, Mohamed

AU - van Nes, Johan

AU - Westerman, Bart A

AU - van Arkel, Jennemiek

AU - Ebus, Marli E

AU - Haneveld, Franciska

AU - Lakeman, Arjan

AU - Schild, Linda

AU - Molenaar, Piet

AU - Stroeken, Peter

AU - van Noesel, Max M

AU - Ora, Ingrid

AU - Santo, Evan E

AU - Caron, Huib N

AU - Westerhout, Ellen M

AU - Versteeg, Rogier

PY - 2012/2/22

Y1 - 2012/2/22

N2 - 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.

AB - 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.

KW - Aging/genetics

KW - Chromosomes, Human/genetics

KW - Cluster Analysis

KW - DNA Helicases/genetics

KW - DNA Mutational Analysis

KW - Gene Expression Regulation, Neoplastic

KW - Genome, Human/genetics

KW - Growth Cones/metabolism

KW - Guanine Nucleotide Exchange Factors/genetics

KW - Humans

KW - Mutation

KW - Neoplasm Staging

KW - Neurites/metabolism

KW - Neuroblastoma/diagnosis

KW - Nuclear Proteins/genetics

KW - Prognosis

KW - T-Lymphoma Invasion and Metastasis-inducing Protein 1

KW - X-linked Nuclear Protein

KW - rac GTP-Binding Proteins/metabolism

KW - rho GTP-Binding Proteins/metabolism

U2 - 10.1038/nature10910

DO - 10.1038/nature10910

M3 - Article

C2 - 22367537

SN - 0028-0836

VL - 483

SP - 589

EP - 593

JO - Nature

JF - Nature

IS - 7391

ER -

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Abstract

Keywords

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