TIAM1
T-lymphoma invasion and metastasis-inducing protein 1 (TIAM-1)
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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.
MeSH Terms
- Aging
- Chromosomes, Human
- Cluster Analysis
- DNA Helicases
- DNA Mutational Analysis
- Gene Expression Regulation, Neoplastic
- Genome, Human
- Growth Cones
- Guanine Nucleotide Exchange Factors
- Humans
- Mutation
- Neoplasm Staging
- Neurites
- Neuroblastoma
- Nuclear Proteins
- Prognosis
- T-Lymphoma Invasion and Metastasis-inducing Protein 1
- X-linked Nuclear Protein
- rac GTP-Binding Proteins
- rho GTP-Binding Proteins