Functional FGFR4 Gly388Arg polymorphism contributes to oral squamous cell carcinoma susceptibility

Abstract

Aberrations of the fibroblast growth factor receptor 4 (FGFR4) genomic region include amplification of FGFR4, activation of FGFR4 kinase domain mutations, and overexpression of FGFR4, which lead to sustained cell proliferation and contribute to tumor development. However, the association between FGFR4 single-nucleotide polymorphisms (SNPs) and risk of oral squamous cell carcinoma (OSCC) remains to be determined. We investigated the relationships between FGFR4 genetic polymorphisms, OSCC development and clinicopathological variables. We recruited a total of 955 patients with OSCC and 1191 controls. Four SNPs of FGFR4 (rs2011077, rs351855, rs7708357, and rs1966265) were examined using real-time polymerase chain reaction. We found that with the rs351855 GA genotype and a combination of the GA and AA genotypes exhibited a 1.431-fold (95% CI: 1.092-1.876) and 1.335-fold (95% CI: 1.033-1.725) higher risk of OSCC. However, patients with OSCC with a homozygous A/A genotype of FGFR4 rs351855 polymorphism had a lower risk of advanced stage OSCC (P = 0.0252). Furthermore, the patients with the FGFR4 rs351855/rs1966265 A-A haplotype had a 2.890-fold (95% confidence interval [CI]: 2.257–3.700) higher risk of OSCC than the controls. Betel quid chewers with the A-A haplotype had a considerably higher risk (95% CI: 16.159–26.937) of OSCC than did betel quid nonchewers with other haplotypes. Moreover, an additional integrated in silico analysis proposed that rs351855 G allele variant to the A allele exhibited a relatively low energy of the transmembrane region. In conclusion, our results suggest that the FGFR4 rs351855 may play a role in susceptibility for OSCC development.

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

“…FGFR4 rs1966265 changes chemotherapy response in breast cancer [ 62 ], higher risk of oral squamous cell carcinoma susceptibility [ 31 ], initiation of cervical cancer (Taiwanese women) [ 19 ], and higher risk of breast cancer in Chinese women of Heilongjiang province [ 16 ]. FGFR4 rs2011077 TC+CC polymorphism is associated with higher tumor stage, tumor size, and grading in urothelial cell carcinoma [ 21 ].…”

“…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.…”

“…Interestingly in the lung normal tissue, genotype-dependent transcriptional profile is present [ 46 ]. In the past few years, there were few epidemiological analysis and meta-analysis focusing on FGFR4 in uterine leiomyomata [ 47 ], hip bone geometry [ 48–50 ], and all types of cancer [ 31 , 51 ]. Our current meta-analysis covers Gly 388 Arg rs351855 G>A and Val 10 Ile rs1966265 polymorphism in FGFR4 polymorphisms to cancer susceptibility and provide wider information in this important regulator of cancers (Rev 1-2).…”

Involvement of FGFR4 Gene Variants on the Clinicopathological Severity in Urothelial Cell Carcinoma

“…For instance, the genome expression may be enhanced due to the activation of a promoter, according to previous research [26]. In a clinical aspect, the SNPs can result in the various influences on diseases development including cancers [12,[27][28][29][30]. In previous studies, SNPs play an important role in the progression and prognosis of UCC via multiple pathways including WNT1-inducible signaling pathway protein 1-, HOX transcript antisense RNA-, and high mobility group box 1 gene-related routes [6,12,31].…”

New concept on association of FGFR4 G388R, V10I polymorphisms and risk of cancer

“…Recently, several studies have concentrated on the relationship between FGFR4 gene variant and the susceptibility of cancer (Chen et al, 2019;Li et al, 2017;Chou et al, 2017;Xiong et al, 2017;Wimmer et al, 2019). A common SNP rs351855, which leads to substitution of glycine by arginine at codon 388 in the domain of EGFR4 receptor (Gly388Arg, G388R), was reported to be associated with cancer risk.…”