Fibroblast Growth Factor Receptor 4 Gly388Arg Research Articles

Abstract 5856: Association between FGFR4 Gly388Arg polymorphism rs351855 or the IDH1 rs11554137 and Japanese gastric cancer

Abstract Introduction: In recent years, certain single-nucleotide polymorphisms (SNPs) have been reported to be associated with increased risk of cancer and prognosis. A Fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism (rs351855) which caused the substitution of arginine for glycine in the transmembrane domain of the receptor, was reported to increase cancer risk or not. The meta-analysis results showed that FGFR4 Gly388Arg polymorphism (rs351855) might be a cancer risk factor for majority Asians, especially in breast cancer and prostate cancer. There is also a report that FGFR4 Gly388Arg polymorphism (rs351855) may be a prognostic biomarker for lung squamous-cell carcinoma patients with lymph node metastasis and uterine cervical cancer. But few studies have been conducted in gastric cancer. And the Isocitrate Dehydrogenase 1 (IDH1) mutations in patients with acute myelogenous leukemia (AML) who have a normal karyotype are associated with a poor prognosis. IDH1 rs11554137:C>T, which is located in codon 105 in the same exon as the IDH1 codon 132 arginine (IDH1R132) mutation, has been described in patients with AML and has been identified as an adverse prognostic factor. It has also been reported that IDH1 rs11554137:C>T has a negative effect on glioblastoma patients in terms of both progression free survival and overall survival (OS). We investigated the association of the gastric cancer with two SNPs. Methods: This study included 30 cases and the tumor samples obtained from gastric cancer patients by surgery between October 2010 and December 2018. We evaluated all 30 samples by a panel testing (OncoGuide NCC Oncopanel system). And we searched for the expression of FGFR4 Gly388Arg polymorphism (rs351855) and the IDH1 rs11554137. Univariate analysis and Kaplan-Meier analysis was performed based on the OS. Comparison between two groups was evaluated using chi-squared test and Fisher's exact test. The stage evaluation of the cancer adopted Japanese Gastric Cancer Association the 15th Edition. Results: Median age is 70 (34-86) years, gender is Male/Female=18/12 cases, histology is Intestinal/diffuse/Scirrhous=8/13/9 cases. There were 21 cases of FGFR4 Gly388Arg polymorphism (rs351855) expression and 2 cases of the IDH1 rs11554137 expression in 30 cases of gastric cancer. The expression of FGFR4 Gly388Arg polymorphism (rs351855) and the IDH1 rs11554137 was compared with various clinic-pathologic factors, however, no significant correlation was found between clinic-pathologic factors and FGFR4 Gly388Arg polymorphism (rs351855) and the IDH1 rs11554137 expression. Conclusion: Our results suggest that neither FGFR4 Gly388Arg polymorphism (rs351855) nor IDH1 rs11554137 is not associated with the progression of gastric cancer. Citation Format: Tomohiro Sera, Masakazu Yashiro, Yurie Yamamoto, Yukako Kushitani, Atsushi Sugimoto, Syuhei Kushiyama, Kenji Kuroda, Shingo Togano, Tomohisa Okuno, Mami Yoshii, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira. Association between FGFR4 Gly388Arg polymorphism rs351855 or the IDH1 rs11554137 and Japanese gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5856.

FGFR4 Gly388Arg Polymorphism Affects the Progression of Gastric Cancer by Activating STAT3 Pathway to Induce Epithelial to Mesenchymal Transition.

PurposeFibroblast growth factor receptor 4 (FGFR4) plays a critical role in cancer progression involving in tumor proliferation, invasion, and metastasis. This study clarified the role of FGFR4-Arg388 variant in gastric cancer (GC), and more importantly highlighted the possibility of this single nucleotide polymorphism (SNP) as potential therapeutic targets.Materials and MethodsFGFR4 polymorphism was characterized in advanced GC patients to perform statistical analysis. FGFR4-dependent signal pathways involving cell proliferation, invasion, migration, and resistance to oxaliplatin (OXA) in accordance with the SNP were also assessed in transfected GC cell lines.ResultsAmong 102 GC patients, the FGFR4-Arg388 patients showed significantly higher tumor stage (p=0.047) and worse overall survival (p=0.033) than the Gly388 patients. Immunohistochemical results showed that FGFR4-Arg388 patients were more likely to have higher vimentin (p=0.025) and p-STAT3 (p=0.009) expression compared with FGFR4-Gly388 patients. In transfected GC cells, the overexpression of FGFR4-Arg388 variant increased proliferation and invasion of GC cells, increasing resistance of GC cells to OXA compared with cells overexpressing the Gly388 allele.ConclusionThe exploration mechanism may be through FGFR4-Arg388/STAT3/epithelial to mesenchymal transition axis regulating pivotal oncogenic properties of GC cells. The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC.

Functional FGFR4 Gly388Arg polymorphism contributes to oral squamous cell carcinoma susceptibility.

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.

FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma

Objective: The aim of this study was to investigate whether fibroblast growth factor receptor 4 (FGFR4) could serve as a potential therapeutic target, prognostic biomarker or biomarker predicting radiotherapy sensitivity in oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC). Methods: FGFR4 immunohistochemistry and FGFR4/CEN5q FISH were performed on tissue microarrays from 212 OSCC and 238 OPSCC patients. FGFR4 genotypes were determined by PCR and DNA sequencing in 76 random OPSCC samples. The response to radiotherapy was evaluated 3 months after the last radiotherapy treatment session by a head and neck radiation oncologist and/or surgeon during clinic visits. The results were correlated to overall survival and response to radiotherapy. Results: The FGFR4 protein was overexpressed in 64% (153/238) of OPSCCs and 41% (87/212) of OSCCs. The FGFR4 gene was amplified in 0.47% (1/212) of OSCCs and 0.42% (1/238) of OPSCCs, and the FGFR4 Gly388Arg polymorphism was detected in 62% (47/76) of OPSCCs. FGFR4 protein expression, FGFR4 gene copy numbers and FGFR4 genotypes were not related to overall survival or response to radiotherapy in OSCC or OPSCC. Conclusion: FGFR4 is frequently overexpressed in OSCC and OPSCC in the absence of gene amplification, and may serve as a potential predictive marker for FGFR4-directed targeted therapy in OSCC and OPSCC.

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<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

Investigation of FGFR4 (Gly388Arg) Gene Polymorphism in Primary Lung Cancer Patients

KEYWORDS Lung Cancer. FGFR4 Gene. Polymorphism. Gly388Arg. Fibroblast ABSTRACT Several studies have shown relationships between predisposition to various types of cancer and polymorphisms of the fibroblast growth factor receptor 4 (FGFR4) gene. In the present study, researchers investigated the relationship between primary lung cancer and (PLC) FGFR4 Gly388Arg polymorphism in regard to tendency, histopathologic sub-type, early onset, and metastatic status. The present study included 124 PLC patients and 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) was used to identify gene polymorphism of FGFR4 Gly388Arg. Statistical significance was considered when p 0.05). The findings in this study demonstrated that there was no relationship between polymorphism of FGFR4 Gly388Arg gene and PLC. However, these results should be confirmed in larger studies and in specific histopathological sub-types of PLC.

Investigation of FGFR4 (Gly388Arg) Gene Polymorphism in Primary Lung Cancer Patients

KEYWORDS Lung Cancer. FGFR4 Gene. Polymorphism. Gly388Arg. Fibroblast ABSTRACT Several studies have shown relationships between predisposition to various types of cancer and polymorphisms of the fibroblast growth factor receptor 4 (FGFR4) gene. In the present study, researchers investigated the relationship between primary lung cancer and (PLC) FGFR4 Gly388Arg polymorphism in regard to tendency, histopathologic sub-type, early onset, and metastatic status. The present study included 124 PLC patients and 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) was used to identify gene polymorphism of FGFR4 Gly388Arg. Statistical significance was considered when p 0.05). The findings in this study demonstrated that there was no relationship between polymorphism of FGFR4 Gly388Arg gene and PLC. However, these results should be confirmed in larger studies and in specific histopathological sub-types of PLC.

The effect of FGFR4 Gly388Arg polymorphism on treatment outcomes after chemoradiotherapy in esophageal cancer patients.

4040 Background: Fibroblast growth factor receptor 4 (FGFR4) has been associated with increased risk, staging, and metastasis in several type of cancer. The purpose of this study was to evaluate the prognostic role of FGFR4 Gly388Arg polymorphism in esophageal cancer after chemoradiotherapy. Methods: Peripheral blood samples from 250 patients who were treated with chemoradiotherapy were used for this study. Patients were diagnosed as a stage of I in 12 (5%), II in 54 (21%), III in 115 (46%) and IV in 69 (28) patients. All of the patients were received chemotherapy using cisplatin and fluorouracil or cisplatin and docetaxel. Results: The overall response was 85%, with 21% complete response and 64% partial response. The overall survival (stage II, 34 months; stage III, 23.3 months; stage IV, 19.3 months, p=0.005) and progression survival (stage II, 23.8 months; stage III, 12.8 months; stage IV, 9 months, p=0.001) was significantly improved according to stage. In FGFR4 genotypic analysis, 96 patients (38.6%)...

Association of the prognostic role of FGFR4 Gly388Arg polymorphism with treatment outcomes after chemoradiotherapy in esophageal cancer.

60 Background: Fibroblast growth factor receptor 4 (FGFR4) has been associated with increased risk, staging, and metastasis in several type of cancer. The purpose of this study was to evaluate the prognostic role of FGFR4 Gly388Arg polymorphism in esophageal cancer after chemoradiotherapy. Methods: Peripheral blood samples from 250 patients who were treated with chemoradiotherapy were used for this study. Patients were diagnosed as a stage of I in 12 (5%), II in 54 (21%), III in 115 (46%) and IV in 69 (28) patients. All of the patients were received chemotherapy using cisplatin and fluorouracil or docetaxel. Results: The overall response was 85%, with 21% complete response and 64% partial response. The overall survival (stage II, 34months; stage III, 23.3 months; stage IV, 19.3 months, p=0.005) and progression survival (stage II, 23.8 months; stage III, 12.8 months; stage IV, 9 months, p=0.001) was significantly improved according to stage. In FGFR4 genotypic analysis, 96 patients (38.6%) were homozygous for Gly388 allele, with 113 heterozygous (45.4%) and 40 (16.0) homozygous for Arg388 allele. There was no significant association between FGFR4 genotype and stage. However, Gly388 allele patients show better overall response rate (90.6%) than Arg388 carriers (82.4%, p=0.050). In early stage (I, II, n=66), Gly388 allele patients tendted to have a better OS (p=0.898) or PFS (p=0.597) than Arg388 carriers. However, in advanced stage (III, IV), the survival outcomes was similar between genotypes. Conclusions: Present study shows that FGFR4 Gly388 allele has a prognostic role in response after chemoradiotherapy in esophageal cancer. Especially in early stage of esophageal cancer, FGFR4 might have an important role in disease progression and survival outcomes. It suggests that the possibility of new therapeutic target for esophageal cancer treatment.

Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients

To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival. Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ(2) test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ(2) test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC. In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ(2) = 3.589, P = 0.166) and alleles (χ(2) = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ(2) = 5.449, P = 0.020), well differentiated (log rank χ(2) = 12.798, P = 0.000), T1 or T2 stage (log rank χ(2) = 4.745, P = 0.029), without lymph node involvement (log rank χ(2) = 6.647, P= 0.010), and at an early clinical stage (log rank χ(2) = 4.615, P = 0.032). Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.

FGFR4 Profile as a Prognostic Marker in Squamous Cell Carcinoma of the Mouth and Oropharynx

BackgroundFibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis.Patients and MethodsDNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays.ResultsPresence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death.ConclusionOur results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx.

Meta and pooled analyses of FGFR4 Gly388Arg polymorphism as a cancer prognostic factor

Fibroblast growth factor receptor 4 (FGFR4) contains a Gly388Arg functional polymorphism (rs351855) that has shown contrasting results in association studies. In this study, we assessed the association between the FGFR4 Gly388Arg polymorphism and cancer prognosis. Meta-analysis and pooled analysis of 6817 and 2537 cancer cases, respectively, were carried out by nodal status and overall survival. The study included the following types of cancer: brain, breast, colorectal, head and neck, larynx, lung, melanoma, prostate, sarcomas. A statistically significant association between the Arg388Arg genotype and nodal involvement was found in the meta-analysis (odds ratio=1.33, 95% confidence interval 1.01-1.74). In the pooled analysis, the Arg388 allele carriers showed an increased hazard of poor overall survival compared with homozygous carriers of the common Gly388 allele, even after adjusting for nodal status (hazard ratio=1.21, 95% confidence interval 1.05-1.40). These results provide evidence of a role for the FGFR4 Gly388Arg polymorphism in modulating patients' outcome in different types of cancer, thus offering to clinicians a new marker to predict predisposition to poor survival in cancer patients.

FGFR4 GLY388ARG polymorphism modulates cancer patients' survival in pooled analysis

Several studies support the hypothesis that patients’ prognosis and survival may be modulated not only by somatic alterations, but also by constitutive genetic factors. Among the few germline variations that have been associated with survival and/or clinical prognostic parameters of cancer patients is the Gly388Arg polymorphism (rs351855) of the fibroblast growth factor receptor 4 (FGFR4) that showed contrasting results in different association studies. Here, we assessed the association between the FGFR4 Gly388Arg polymorphism and cancer prognosis carrying out a meta- and pooled analyses of 6,028 and 2,537 cancer cases, respectively, by nodal status, clinical stage, and overall survival. A statistically significant association between FGFR4 Arg388Arg homozygosity and nodal status was found in the meta-analysis but not in the pooled analysis adjusted for confounding factors. In the pooled analysis, Gly388Arg heterozygous carriers showed an increased hazard of poor overall survival as compared to homozygous carriers of the common Gly388 allele, even after adjusting for clinical stage or nodal status (HR = 1.24, 95% CI 1.06 – 1.45). These results provide evidence of a role for the FGFR4 Gly388Arg polymorphism in modulating patients' outcome in different types of cancer. The tight linkage disequilibrium of the polymorphism with missense and intronic single nucleotide polymorphisms of the FGFR4 locus might explain the contradictory associations of this polymorphism with patient outcome reported thus far.

The Fibroblast Growth Factor Receptor-4 Arg388 Allele is Associated with Gastric Cancer Progression

Fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism, located in the FGFR4 gene exon 9, was reported to be associated with malignant tumors prognosis; however, there has been no relevant research for gastric cancer. The purpose of this study was to investigate the clinical significance of FGFR4 Gly388Arg polymorphism as well as the mRNA expression of FGFR4 in patients with gastric cancer. The mRNA expression of FGFR4 in 103 gastric cancer tissues and corresponding normal tissues were measured by reverse transcription polymerase chain reaction (PCR) and real-time quantitative PCR. PCR-restriction fragment length polymorphism analysis was performed to detect the FGFR4 Gly388Arg in 103 gastric cancer tissues. In 57.3% of patients, homozygous or heterozygous Arg388 allele was present. FGFR4 expressions in mRNA levels were higher in gastric cancer tissues compared with those in relevant normal tissues. However, there is no significantly statistical difference compared with mRNA expression of FGFR4 in different genotypes. Associations between FGFR4 Gly388Arg polymorphism and overall survival exist in patients with gastric cancer (P = 0.046).The FGFR4 Arg allele (hazard risk (HR), 2.324; 95% confidence interval (CI), 1.054-4.125; P = 0.037) and TNM stage (HR, 5.516; 95% CI 3.658-7.409; P = 0.005) were independent prognostic factors in patients with gastric cancer. Based on this study, FGFR4 Arg388 genotype-a marker for gastric cancer progression-may predict prognosis of gastric cancer.

FGFR4 transmembrane domain polymorphism and cancer risk: A meta-analysis including 8555 subjects

Fibroblast growth factor receptor 4 (FGFR4), belonging to the receptor tyrosine kinase family, is involved in cancer initiation and progression. The FGFR4 Gly388Arg polymorphism in the transmembrane domain of the receptor was shown to contribute to genetic susceptibility to cancer but the results were inconsistent. We performed a meta-analysis using 12 eligible case-control studies with a total of 4892 patients and 3663 controls to summarise the data on the association between the FGFR4 Gly388Arg polymorphism and cancer risks. The overall odds ratio (OR) with a 95% confidence interval (CI) showed statistical association between the FGFR4 Gly388Arg polymorphism and cancer risks under homozygote comparison, allele contrast and the recessive genetic model. In the subgroup analysis by ethnicity, statistically significantly increased cancer risks were found among Asians for homozygote comparison (OR = 1.43, 95% CI = 1.13–1.80, P heterogeneity = 0.24), allele contrast (OR = 1.16, 95% CI = 1.04–1.29, P heterogeneity = 0.25) and the recessive genetic model (OR = 1.47, 95% CI = 1.19–1.81, P heterogeneity = 0.15). In the subgroup analysis for different tumour types, Arg 388 allele had an effect of increasing the risks of breast (homozygote comparison OR = 1.57, 95% CI = 1.04–2.37, P heterogeneity = 0.83 and the recessive model OR = 1.51, 95% CI = 1.02–2.24, P heterogeneity = 0.80) and prostate cancer (Gly/Arg versus Gly/Gly: OR = 1.16, 95% CI = 1.02–1.32, P heterogeneity = 0.74; Arg versus Gly: OR = 1.17, 95% CI = 1.07–1.29, P heterogeneity = 0.18 and the dominant model: OR = 1.20, 95% CI = 1.06–1.35, P heterogeneity = 0.89). Our meta-analysis suggests that the FGFR4 Gly388Arg polymorphism most likely contributes to susceptibility to cancer, especially in Asians. Besides, the Arg 388 allele might be associated with increased risks of breast and prostate cancer.

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 and prostate cancer risk in Scottish men

Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan.

Association of the fibroblast growth factor receptor-4 (FGFR4) Gly388Arg polymorphism with clinical and pathological response to primary systemic therapy (PST) for early breast cancer (EBC)

525 Background: The FGFR4 Arg388 genotype has recently been shown to be associated with decreased disease free survival after adjuvant systemic therapy for EBC and thus therapy resistance (Harbeck et al, J Clin Oncol. 2006). Primary systemic therapy (PST) for EBC allows in-vivo chemosensitivity testing. Pathological complete response (pCR) in the breast following PST is associated with improved survival. We evaluated the FGFR4 Gly388Arg polymorphism as a predictive factor for response to PST for EBC in the setting of a prospective, randomized phase 2 trial. Methods: Patients (pts, n = 257) with T2–4/N0–2/M0 EBC were randomized to 4 cycles (cy) A 60 mg/m2 + C 600 mg/m2 day (d) 1 every three weeks (q3w) followed by 4 cy D 100 mg/m2 d1 q3w, or 4 cy A 60 mg/m2 + P 500 mg/m2 on d1 q3w followed by 4 cy D 100 mg/m2 d1 q3w, stratified by hormone receptor (HR) status. Surgery was performed after last chemotherapy. Genotyping was performed using a Taqman Genotyping assay. The genotype was confirmed by RFLP-PCR for 50% of samples with 100% congruence. Results: Genotype was available for 252 of 257 pts enrolled into this study. Using Fisher´s Exact Test there was no correlation between genotype and clinical tumour size (cT), HR status, HER2neu status, grading, menopausal status or triple negative phenotype. The G/G genotype correlates significantly with clinically positive axillary lymph nodes before chemotherapy (p = 0.03). Considering all pts the G/G genotype (vs G/A + A/A) is associated with a significantly lower overall response rate (ORR)(OR 0,47; 65% vs 80%; p = 0.03). Separate analysis of treatment arms showed a significant correlation between the G/G genotype (vs other genotypes) and a lower pCR rate (OR 0.33; 12.5% vs 30.4%; p = 0.04), clinical complete response (p = 0.02) and ORR (OR 0.25; p = 0.01) in the AC-D arm, whereas there was no correlation for pts treated with AP-D. Conclusions: This study provides important evidence that the FGFR4 genotype might serve as a valuable predicitve marker for response to PST with AC-D for EBC. No significant financial relationships to disclose.

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.