TIAM1

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T-lymphoma invasion and metastasis-inducing protein 1 (TIAM-1)

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Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

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