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 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 multi-vesicular 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.

FunctionalFGFR4Gly388Arg polymorphism contributes to cancer susceptibility: Evidence from meta-analysis

“…After full review, 91 articles were excluded for the following reasons: 1) they were review articles or meta-analyses, 2) they did not investigate association between the FGFR4 rs351855 G>A polymorphism and cancer risk, 3) they were not case-control studies, or 4) had no enough data reported to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). One article was further excluded because of the departure from Hardy–Weinberg equilibrium (HWE) [ 32 ]. Only 23 articles consisting of 27 individual studies investigated the association between the FGFR4 rs351855 G>A polymorphism and cancer risk, and fit the eligibility criteria (Figure 1 ).…”

Overview and recent advances in the treatment of neuroblastoma

“…Genome-wide association studies (GWAS) have also identified additional germline genetic variants in neuroblastoma patients, including single-nucleotide polymorphisms in LIN28B, BARD1, and LMO1, among others [26][27][28][29] as well as other polymorphisms in other chromosomal regions yet to be fully characterized [30,31]. These polymorphisms occur relatively frequently in the general population and may contribute to the development of sporadic neuroblastoma, although the functional roles of these germline variants and other somatic alterations remain to be elucidated.…”

An updated meta-analysis of the association between fibroblast growth factor receptor 4 polymorphisms and susceptibility to cancer

“…A common nonsynonymous single nucleotide polymorphism (SNP) at codon 388 (rs351855 G>A) in exon 9, which results in a change of glycine to arginine (Gly 388 Arg), was recognized in the transmembrane domain of the EGFR4 receptor [ 13 ]. Several studies inspected the relationship between FGFR4 gene rs351855 G>A polymorphism and numerous types of cancer including breast cancer [ 13–18 ], cervical cancer [ 19–21 ], colon cancer [ 13 , 18 , 22 ], gastric cancer [ 23 ], prostate cancer [ 24–27 ], head and neck squamous cell carcinoma (HNSCC) [ 28 , 29 ], oral squamous cell carcinoma (OSCC) [ 30 , 31 ], lung cancer [ 32–34 ], hepatocellular carcinoma [ 35–37 ], sarcoma [ 38 ], skin cancer [ 39 ], neuroblastoma [ 40 ], non-Hodgkin’s lymphoma [ 41 ], and glioma [ 42 ]. There are few direct reports about the effect of FGFR4 polymorphism on the gene expression.…”

“…FGFR4 rs351855 polymorphism induced higher expression of FGFR4 protein and worse prognosis in breast cancer [ 43 ]. It has been reported that the rate of degradation of the Arg 388 receptor was slower than the Gly 388 receptor in neuroblastoma cells and also initiated internalization of the receptor into multivesicular structures (Rev1-1) [ 40 ]. In another investigation, the researchers showed that expression of the FGFR4 Arg 388 protein activated the extracellular signal-related kinase pathway with subsequent expression of several genes which were associated with the aggressive form of prostate cancer [ 44 ], (Rev1-1).…”