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In-Silico Analysis of Deleterious SNPs of FGF4 Gene and Their Impacts on Protein Structure, Function and Bladder
Ee Chen Lim1, Shu Wen Lim1, Kenneth JunKai Tan1
1Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia.
Abstract:
Dysregulation of fibroblast growth factors is linked to the pathogenesis of bladder cancer. The role of FGF1 and FGF3 is evident in bladder cancer; however, the role of FGF4 is vague. Despite being reported that FGF4 interacts with FGF1 and FGF3 in MAPK pathways, its pathogenesis and mechanism of action are yet to be elucidated. Therefore, this study aimed to elucidate pathogenic nsSNPs and their role in the prognosis of bladder cancer by employing in-silico analysis. The nsSNPs of FGF4 were retrieved from the NCBI database. Different in silico tools, PROVEAN, SIFT, PolyPhen-2, SNPs&GO, and PhD-SNP, were used for predicting the pathogenicity of the nsSNPs. Twenty-seven nsSNPs were identified as “damaging”, and further stability analysis using I-Mutant 2.0 and MUPro indicated 22 nsSNPs to cause decreased stability (DDG scores < −0.5). Conservation analysis predicted that Q97K, G106V, N164S, and N167S were highly conserved and exposed. Biophysical characterisation indicated these nsSNPs were not tolerated, and protein-protein interaction analysis showed their involvement in the GFR-MAPK signalling pathway. Furthermore, Kaplan Meier bioinformatics analyses indicated that the FGF4 gene deregulation affected the overall survival rate of patients with bladder cancer, leading to prognostic significance. Thus, based on these analyses, our study suggests that the reported nsSNPs of FGF4 may serve as potential targets for diagnoses and therapeutic interventions focusing on bladder cancer.
Insights
Fibroblast Growth Factor 4 (FGF4) gene variants may impact bladder cancer development and patient survival. These specific genetic alterations could offer new diagnostic and therapeutic targets for bladder cancer.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- Fibroblast Growth Factors (FGFs) are implicated in bladder cancer pathogenesis.
- While FGF1 and FGF3 roles are known, FGF4's involvement in bladder cancer remains unclear.
- FGF4's interaction with FGF1 and FGF3 in MAPK pathways necessitates further investigation into its pathogenic mechanisms.
Purpose of the Study:
- To identify pathogenic non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in the FGF4 gene.
- To investigate the role of these nsSNPs in the prognosis of bladder cancer.
- To elucidate the potential mechanism of action of pathogenic FGF4 nsSNPs.
Main Methods:
- Retrieved FGF4 nsSNPs from the NCBI database.
- Utilized multiple in silico tools (PROVEAN, SIFT, PolyPhen-2, SNPs&GO, PhD-SNP) for pathogenicity prediction.
- Performed stability analysis (I-Mutant 2.0, MUPro), conservation analysis, biophysical characterization, protein-protein interaction analysis, and Kaplan Meier survival analysis.
Main Results:
- Identified 27 damaging nsSNPs in FGF4; 22 caused decreased protein stability.
- Highlighted Q97K, G106V, N164S, and N167S as highly conserved, exposed, and non-tolerated nsSNPs involved in the GFR-MAPK signaling pathway.
- Demonstrated that FGF4 gene deregulation significantly impacts overall survival rates in bladder cancer patients.
Conclusions:
- Specific nsSNPs in the FGF4 gene are associated with decreased protein stability and are potentially pathogenic in bladder cancer.
- These identified FGF4 nsSNPs are linked to the GFR-MAPK signaling pathway and affect patient prognosis.
- The study suggests FGF4 nsSNPs as potential diagnostic and therapeutic targets for bladder cancer.
