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Published on: August 15, 2019
Prevalence and functional consequence of PHOX2B mutations in neuroblastoma
E H Raabe1, M Laudenslager, C Winter
1Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
Oncogene
|July 20, 2007
Summary
PHOX2B gene mutations are a rare cause of hereditary neuroblastoma. These mutations disrupt neurodevelopmental pathways, impairing tumor cell differentiation and suggesting complex genetics in neuroblastoma initiation.
Area of Science:
- Genetics
- Developmental Biology
- Oncology
Background:
- PHOX2B is crucial for peripheral nervous system development and a key gene in congenital central hypoventilation syndrome (CCHS).
- Germline PHOX2B alterations have been linked to neuroblastoma in patients with CCHS or Hirschsprung disease.
- A comprehensive analysis of PHOX2B mutation frequency and functional impact in neuroblastoma was lacking.
Purpose of the Study:
- To investigate the frequency and functional consequences of PHOX2B mutations in hereditary neuroblastoma.
- To explore the role of PHOX2B in neuroblastoma development and differentiation.
Main Methods:
- Screening of germline PHOX2B mutations in a large cohort of hereditary neuroblastoma cases.
- Analysis of PHOX2B mutations in neuroblastoma cell lines and primary sporadic tumors.
- Functional studies involving overexpression of wild-type and mutant PHOX2B in neuroblastoma cell lines.
Main Results:
- Germline PHOX2B mutations were identified in 6.4% of individuals with a genetic predisposition to neuroblastoma.
- Mutations were found in neuroblastoma cell lines but not in sporadic primary tumors.
- Wild-type PHOX2B suppressed proliferation and promoted differentiation, while patient-derived mutants failed to promote differentiation.
Conclusions:
- PHOX2B alterations are an infrequent cause of hereditary neuroblastoma.
- Disruption of PHOX2B's role in neurodevelopment can hinder terminal differentiation in neuroblastoma.
- The genetics of neuroblastoma are complex, with genes involved in noradrenergic development being potential predisposition factors.
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