A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation
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Updated: Mar 26, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Sarah B Whittle1, Sahily Reyes, Melissa Du
1*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.
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.
Materials And 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.
Insights
The FGFR4 Arg388 polymorphism is linked to a higher prevalence of childhood neuroblastoma, potentially due to altered receptor degradation rates. This finding highlights FGFR4
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Neuroblastoma, a pediatric cancer, has poor outcomes, necessitating research into its pathogenesis.
- Aberrant growth factor receptor signaling, particularly receptor tyrosine kinases, is implicated in various cancers.
- A specific germline polymorphism in the FGFR4 gene is linked to poor outcomes in several malignancies.
Purpose of the Study:
- To investigate the role of the FGFR4 Gly/Arg388 polymorphism in the development of neuroblastoma.
- To determine if this polymorphism is associated with neuroblastoma patient outcomes and prognostic features.
Main Methods:
- Assessed germline DNA from neuroblastoma patients and controls for the FGFR4 Gly/Arg388 polymorphism using RT-PCR.
- Analyzed allele frequencies for associations with neuroblastoma outcomes and prognostic features.
- Measured degradation and internalization rates of FGFR4 Arg388 and Gly388 receptors.
Main Results:
- The FGFR4 AA genotype and A allele were significantly more prevalent in neuroblastoma patients compared to controls.
- The Arg388 FGFR4 receptor exhibited slower degradation and reduced internalization into multivesicular bodies in neuroblastoma cells compared to the Gly388 receptor.
Conclusions:
- The FGFR4 Arg388 polymorphism is associated with an increased prevalence of childhood neuroblastoma.
- Differences in FGFR4 degradation rates may underlie this association.
- This study establishes a role for FGFR4 in neuroblastoma pathogenesis, suggesting its genotype and regulatory pathways are relevant targets.
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