title: A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation.
abstract: BACKGROUND
  Outcomes for children with high-risk neuroblastoma are poor, and improved understanding of the mechanisms underlying neuroblastoma pathogenesis, recurrence, and treatment resistance will lead to improved outcomes. Aberrant growth factor receptor expression and receptor tyrosine kinase signaling are associated with the pathogenesis of many malignancies. A germline polymorphism in the FGFR4 gene is associated with increased receptor expression and activity and with decreased survival, treatment resistance, and aggressive disease for many malignancies. We therefore investigated the role of this FGFR4 polymorphism in neuroblastoma pathogenesis.
  
  
  METHODS
  Germline DNA from neuroblastoma patients and matched controls was assessed for the FGFR4 Gly/Arg388 polymorphism by RT-PCR. Allele frequencies were assessed for association with neuroblastoma patient outcomes and prognostic features. Degradation rates of the FGFR4 Arg388 and Gly388 receptors and rates of receptor internalization into the late endosomal compartment were measured.
  
  
  RESULTS
  Frequency of the FGFR4 AA genotype and the prevalence of the A allele were significantly higher in patients with neuroblastoma than in matched controls. The Arg388 receptor demonstrated slower degradation than the Gly388 receptor in neuroblastoma cells and reduced internalization into multivesicular bodies.
  
  
  CONCLUSIONS
  The FGFR4 Arg388 polymorphism is associated with an increased prevalence of neuroblastoma in children, and this association may be linked to differences in FGFR4 degradation rates. Our study provides the first evidence of a role for FGFR4 in neuroblastoma, suggesting that FGFR4 genotype and the pathways regulating FGFR4 trafficking and degradation may be relevant for neuroblastoma pathogenesis.
authors: *Section of Hematology-Oncology, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine †Department of Neurobiology and Anatomy, University of Texas Medical School ‡Department of Pathology & Immunology, Baylor College of Medicine and Michael E. DeBakey VAMC, Houston, TX.
authors: Sarah B
authors: SB
authors: Whittle
authors: Sahily
authors: S
authors: Reyes
authors: Melissa
authors: M
authors: Du
authors: Monica
authors: M
authors: Gireud
authors: Linna
authors: L
authors: Zhang
authors: Sarah E
authors: SE
authors: Woodfield
authors: Michael
authors: M
authors: Ittmann
authors: Michael E
authors: ME
authors: Scheurer
authors: Andrew J
authors: AJ
authors: Bean
authors: Peter E
authors: PE
authors: Zage
mesh_terms: D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism*; D012307:Risk Factors
chemical_list: C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4