Fibroblast Growth Factor Receptor 4 Polymorphism Research Articles

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

Fibroblast growth factor receptor 4 (FGFR4) is a cell surface receptor tyrosine kinases (RTKs) for FGFs.Several studies have focused on the association between FGFR4 polymorphisms and cancer development. This meta-analysis aimed to estimate the association between FGFR4 rs351855 (Gly388Arg), rs1966265 (Val10Ile), rs7708357, rs2011077, and rs376618 polymorphisms and cancer risk. Eligible studies were identified from electronic databases. All statistical analyses were achieved with the STATA 14.0 software. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to quantitatively estimate the association. Overall, no significant association was found among rs351855, rs2011077, and rs376618 polymorphisms with the risk of overall cancer. The rs1966265 polymorphism significantly decreased the risk of cancer in recessive (OR = 0.87, 95% CI = 0.78–0.97, P=0.009, TT vs CT+CC) genetic model. Whereas the rs7708357 polymorphism was positively associated with cancer risk in dominant (OR = 1.17, 95% CI = 1.02–1.36, P=0.028) genetic model. Stratified analysis revealed that rs351855 variant significantly increased the risk of prostate cancer in heterozygous (OR = 1.16, 95% CI = 1.02–1.32, P=0.025 AG vs GG), dominant (OR = 1.20, 95% CI = 1.06–1.35, P=0.004, AG+AA vs GG), and allele (OR = 1.22, 95% CI = 1.06–1.41, P=0.005, A vs G) genetic models.In summary, the findings of this meta-analysis indicate that rs1966265, rs7708357, and rs351855 polymorphisms are correlated to cancer development. Further well-designed studies are necessary to draw more precise conclusions.

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

Fibroblast growth factor receptor 4 (FGFR4) plays a prominent role in cell proliferation and cancer progression. This study explored the effect of FGFR4 single-nucleotide polymorphisms (SNPs) on the clinicopathological characteristics of urothelial cell carcinoma (UCC). This study was conducted to survey the possible correlation of the polymorphism of FGFR4 to the risk and clinicopathologic characteristics of UCC. Four loci of FGFR4 (rs2011077 T > C, rs351855 G > A, rs7708357 G>A, and rs1966265 A > G) were genotyped via the TaqMan allelic discrimination approach in 428 UCC cases and 856 controls. The results indicated that UCC subjects who carried the SNP rs2011077 TC+CC genotypes were significantly related to a higher tumor stage (odds ratio (OR): 1.751, 95% confidence interval (CI): 1.078–2.846), primary tumor size (OR: 1.637, 95% CI: 1.006–2.662), and histopathologic grading (OR: 1.919, 95% CI: 1.049–3.511). Moreover, the SNP rs1966265 AG+GG genotypes were prominently related to a higher tumor stage (OR: 1.769, 95% CI: 1.082–2.891), primary tumor size (OR: 1.654, 95% CI: 1.011–2.706), and histopathologic grading (OR: 2.006, 95% CI: 1.096–3.674) compared to individuals with AA homozygotes. In conclusion, our data reveal association of FGFR4 polymorphisms with UCC clinicopathologic characteristics. FGFR4 polymorphisms may serve as a marker or therapeutic target in UCC development.

Prognostic implications of fibroblast growth factor receptor 4 polymorphisms in primary breast cancer.

Fibroblast growth factor receptor 4 (FGFR4) belongs to the receptor tyrosine kinase (RTK) family, and FGFR4 polymorphisms have been implicated in both normal development and cancer, including breast cancer. In the present study, we investigated correlations between polymorphisms in FGFR4 and breast cancer prognosis. The FGFR4 SNPs rs1966265 and rs351855 were genotyped in 747 breast cancer patients using the SNaPshot method. FGFR4 protein expression was detected by immunohistochemistry in 339 samples. SNP rs351855 was correlated with FGFR4 protein expression under dominant and co-dominant models. Lymph node metastasis (LNM), ER (estrogen receptor) status, and molecular subtype were associated with high FGFR4 expression. Univariate analysis revealed rs351855 (CC/CT: P = 0.027, CC/TT: P < 0.001, CC/CT + TT: P = 0.005) to be a prognostic predictor, and multivariate analysis indicated rs351855 (CC/TT: P = 0.005) to be an independent prognostic factor. Kaplan-Meier survival analysis showed that high FGFR4 protein expression was associated with a poor prognosis. SNP rs351855 was correlated with worse outcomes, with a dose-dependent effect. The results of this study show that FGFR4 SNP rs351855 is associated with up-regulation of FGFR4 protein expression and a worse prognosis in breast cancer.

FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition.

PurposeFibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism.Materials and MethodsFGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines.ResultsAmong a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele.ConclusionThe Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

Abstract 3407: FGFR4 Arg388 polymorphism is a poor prognostic factor for resected stage III colon cancer

Abstract Purpose To evaluate the prognostic role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in patients with surgically resected stage III colon cancer. Patients and Methods FGFR4 polymorphism was checked in peripheral blood from 273 patients who received curative resection and diagnosed as stage III colon cancer. Genomic DNA was extracted from blood which was drawn before curative resection. FGFR4 Gly388Arg genotyping was carried out using high-resolution melting (HRM) analysis. Results In total 273 patients, 92 patients (34%) were homozygous for Gly388 allele, with 146 heterozygous (54%) and 35 homozygous (13%) for Arg388. No significant association was found between clinical or histopathologic tumor characteristics and FGFR4 genotype. In survival analysis, Gly388 allele showed better 3Y-DFS than Arg388 carriers (heterozygous or Arg388 homozygous) in patients with no adjuvant (p = 0.26) or 5-FU/LV treated (p = 0.038). However, patients receiving adjuvant FOLFOX showed similar 3Y-DFS regardless of genotype. In addition, 5Y-OS was found significant improvement in Gly388 allele compared with Arg388 carriers (92.5% vs. 74.9%, p = 0.04) regardless of adjuvant treatment. In univariate analysis, age, N stage, tumor differentiation, lymphocyte response, adjuvant chemotherapy and FGFR4 genotype were associated with poor OS. In multivariate analysis, FGFR4 Arg388 carriers (HR 5.17; 95% CI, 2.06-12.92, p&amp;lt;0.001) showed significantly poor prognostic factors for OS together with age (≥ 70Y), N stage, poorly differentiation, absence of lymphocyte response, no adjuvant chemotherapy. Conclusion FGFR4Arg388 polymorphism is an independent poor prognostic factor in surgically resected stage III colon cancer. This result could guide the individual selection for adjuvant chemotherapy and potential therapeutic target for surgically resected stage III colon cancer. Citation Format: Sang-Hee Cho, Min-Ho Shin, Sun-Seog Kweon, Hee-Nam Kim, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung. FGFR4 Arg388 polymorphism is a poor prognostic factor for resected stage III colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3407. doi:10.1158/1538-7445.AM2015-3407

Fibroblast growth factor receptor 4 polymorphism is associated with increased risk and poor prognosis of non-Hodgkin’s lymphoma

Fibroblast growth factor receptor 4 (FGFR4) is expressed in various cell types and plays important roles in regulating immune responses. Evidence has shown that FGFR4 rs351855 (Gly388Arg) polymorphism may act as a risk factor for many diseases. In the current study, we investigated the association between FGFR4 polymorphisms and the susceptibility to non-Hodgkin's lymphoma (NHL) in the Chinese population. Two polymorphisms in the FGFR4 gene (rs351855G/A and rs147603016G/A) were detected by polymerase chain reaction-restriction fragment length polymorphism in 421 NHL cases and 486 healthy controls. Results showed that prevalence of rs351855AA genotype was significantly increased in patients than in controls (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.91-3.23, P < 0.001). Similarly, rs351855A allele presented significantly higher numbers in cases compared to healthy donors (49.8 versus 40.1%, P < 0.001). Further study revealed that the frequency of the rs351855G/A polymorphism was clearly elevated in cases with B cell subtype than those with T cell subtypes. When analyzing the survival time of NHL patients with FGFR4 rs351855G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients with GG genotype (P < 0.001) or GA genotype (P < 0.001). These results suggest that FGFR4 rs351855G/A polymorphism is associated with increased susceptibility to NHL and could be used as a marker for predicting the prognosis of the malignancy.

Fibroblast growth factor receptor 4 Gly388Arg polymorphism associated with severity of gallstone disease in a Chinese population

The etiology of gallstone disease is multifactorial; supersaturation of bile with cholesterol is a primary cause for gallstone formation. In previous studies, we found that fibroblast growth factor receptor 4 (FGFR4) plays an important role in maintaining bile acid homeostasis by regulating the expression of cholesterol 7α-hydroxylase (CYP7A1), a rate-limiting enzyme for bile acid biosynthesis. The Gly388Arg (G-388R) polymorphism of FGFR4 affects stabilization and activation of FGFR4. Consequently, we studied the FGFR4 gene as a candidate gene for genetic susceptibility to gallstone disease. We found that overexpression of FGFR4, especially the G-388R mutant of FGFR4, inhibits luciferase activity of CYP7A1 reporter in HepG2 cells, indicating that the G-388R mutant of FGFR4 may have greater inhibitory activity against bile acid biosynthesis. To investigate the association of FGFR4 polymorphism with gallstone disease, 117 patients with gallstone disease and 457 controls were genotyped for FGFR4 polymorphism G-388R by PCR-RFLP. Although the incidence of gallstone disease was not greater in patients with the FGFR4 RR genotype, the ratio of gallstone patients with acute cholecystitis in the FGFR4 RR genotype (42%) was significantly higher than that in other genotypes of FGFR4 (P = 0.019). In conclusion, the FGFR4 polymorphism is a genetic risk factor contributing to aggravation of gallstone disease.

Association between fibroblast growth factor receptor 4 polymorphisms and risk of hepatocellular carcinoma

Human fibroblast growth factor receptor 4 (FGFR4) polymorphisms have recently been shown to be associated with tumor progression of various types of cancer, including cancer of the breast, colon, and prostate and sarcoma. However, their association with hepatocellular carcinoma (HCC) is unknown. We evaluated the association of FGFR4 polymorphisms with risk of HCC in a study population with HCC and with/without hepatitis B virus (HBV) infection in East China. We genotyped four FGFR4 SNPs (rs351855, rs641101, rs376618, and rs31777) in 1,451 Chinese subjects, including 711 patients with HCC, 368 controls with HBV infection and 372 controls without HBV infection, using the TaqMan genotyping assay. Unconditional logistic regression analysis was performed to evaluate associations of genotypes of each SNP with HCC risk. For the rs351855 (Arg388) locus, we observed a reduced HCC risk associated with the T variant genotypes, particularly for those whose tumors with gross portal vein tumor thrombosis (gross PVTT) (OR = 0.66; 95% confidence interval, 95% CI = 0.46-0.95 for CT + TT). Such a protective effect was also observed for those with liver cirrhosis (OR = 0.42; 95% CI = 0.20-0.88 for CT + TT). Clearly the T allele was associated with these conditions. Our findings suggest that genetic polymorphism in FGFR4 may be a marker for risk of HCC with liver cirrhosis and gross PVTT in Chinese populations.

Association between Fibroblast Growth Factor Receptor-4 Gene Polymorphism and Risk of Prostate Cancer: A Meta-Analysis

Objectives: To examine the association between fibroblast growth factor receptor-4 (FGFR-4) genetic polymorphisms (Gly-388Arg) and prostate cancer susceptibility. Methods: A comprehensive search was conducted to identify all case-control studies of FGFR-4 polymorphisms and prostate cancer risk. Statistical analysis was performed with the software program Stata, version 8.0, and Review Manage, version 4.2. Results: A total of 4 eligible studies, including 2,618 cases and 2,305 controls, relating the FGFR-4 polymorphism to the risk of prostate cancer were identified. The overall results indicated a significant association between FGFR-4 polymorphisms and prostate cancer. In the subgroup analysis by ethnicity, a significant association was found between European descent for recessive model (random effects OR 0.82, 95% CI 0.72–0.93) and co-dominant genetic model (random effects OR 0.83, 95% CI 0.68–1.00). Sensitivity analysis also found a significant association in the recessive (random effects OR 0.68, 95% CI 0.49–0.95) or the co-dominant (random effects OR 0.68, 95% CI 0.49–0.96) models. Egger’s test showed that publication bias was not present in any of the comparisons. Conclusions: Gly-388Arg polymorphism of FGFR-4 most likely contributes to susceptibility to prostate cancer, especially in men of European descent.

FGFR4 polymorphism, TP53 mutation, and their combinations are prognostic factors for oral squamous cell carcinoma.

The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung

The association of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism with clinical stage and overall survival in a series of 541 Italian lung adenocarcinoma (ADCA) patients indicated a significantly decreased survival in patients carrying the rare Arg388 allele as compared to that in Gly/Gly homozygous patients [hazard ratio (HR) = 1.5; 95% confidence interval (CI) 1.1-1.9], with the decrease related to the association of the same polymorphism with clinical stage (HR = 1.8, 95% CI 1.3-2.6). By contrast, no significant association was detected in small series of either Norwegian lung ADCA patients or Italian lung squamous cell carcinoma (SQCC) patients. Single nucleotide polymorphisms of known FGFR4 ligands expressed in lung (FGF9, FGF18 and FGF19) were not associated with clinical stage or survival and showed no interaction with FGFR4. Analysis of gene expression profile in normal lungs according to FGFR4 genotype indicated a specific transcript pattern associated with the allele carrier status, suggesting a functional role for the FGFR4 polymorphism already detectable in normal lung. These findings confirm the significant association of the FGFR4 Gly388Arg polymorphism with clinical stage and overall survival in an Italian lung ADCA population and demonstrate a FGFR4 genotype-dependent transcriptional profile present in normal lung tissue.

Polymorphism of FGFR4 Gly388Arg Does Not Confer an Increased Risk to Breast Cancer Development

The genotype analysis of the Gly and Arg allele at codon 388 of fibroblast growth factor receptor-4 (FGFR4) gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. The aim of the present study was to evaluate the association between the FGFR4 Gly388Arg polymorphism and breast cancer risk as well as clinicopathological parameters of the patients. The Gly/Gly, Gly/Arg, Arg/Arg, and Arg allele genotypes were detected in 46.3%, 44.4%, 9.3%, and 53.7% of breast cancer cases, respectively. The distribution of genotype (p = 0.204) and allele (p = 0.086) frequencies of FGFR4 polymorphism were not significantly different between the breast cancer cases and normal individuals. Women who were Arg/ Arg homozygotes (OR = 1.714, 95% CI 0.896-3.278), Gly/Arg heterozygotes (OR = 1.205, 95% CI 0.863-1.683), carriers of Arg allele genotype (OR = 1.269, 95% CI 0.921-1.750), or Arg allele (OR = 1.246, 95% CI 0.970-1.602) were not associated with breast cancer risk. The Arg allele genotype was significantly associated with lymph node metastases (p = 0.001) but not with other clinicopathological parameters. Our findings suggest that the polymorphic variant at codon 388 of FGFR4 gene does not confer increased risk to breast cancer development but it may be a potential genetic marker for tumor prognosis.

Functional FGFR4 Gly388Arg Polymorphism Predicts Prognosis in Lung Adenocarcinoma Patients

Fibroblast growth factor receptor 4 (FGFR4) is a member of a family of transmembrane receptors with ligand-induced tyrosine kinase activity. The Gly388Arg polymorphism in the FGFR4 gene was reported to modulate cancer cell migration in vitro and to be associated with breast, colon, and prostate cancer prognostic parameters. The purpose of this study was to investigate the involvement of the FGFR4 polymorphism in lung tumorigenesis. A case-control study was performed including 274 patients with histologically confirmed lung adenocarcinoma and 401 healthy control subjects from general population. mRNA expression analysis was carried out in healthy lung of cancer patients. Patients with the Arg/Arg or Gly/Arg genotype compared to those with a Gly/Gly genotype had an earlier age at cancer onset (median age, 60.2 v 63.4 years), higher proportion of poor clinical stage disease (hazard ratio [HR], 2.3; 95% CI, 1.4 to 3.9; P = .002), of nodal involvement (HR, 1.9; 95% CI, 1.1 to 3.2; P = .027), or of short-term survivors (HR, 1.6; 95% CI, 1.1 to 2.3; P = .008). In healthy lungs, FGFR4 did not show allele-specific expression and mRNA levels were not associated with genotype. This study suggests that FGFR4 Gly388Arg polymorphism may predict prognosis in lung adenocarcinoma.