The fibroblast growth factor receptors (FGFRs), a subfamily of transmembrane receptor tyrosine kinase (RTK), composed of four related members (FGFR1-4) (1, 2). The activation of FGFR pathway by binding of various ligands to FGFRs triggers several downstream cascades and then activates multiple signal transduction pathways, including the STAT, PI3K/Akt, Ras/Raf/MapK, and phospholipase Cγ (1, 3–5). These signaling pathways regulate a variety of cellular functions such as cell survival, proliferation, migration, differentiation, angiogenesis, and epithelial-mesenchymal transition, and can thereby involve in carcinogenesis (4–6). Actually, numerous studies have demonstrated the aberrant activation of FGFR signaling in carcinogenesis. A recent analysis of 4,853 tumors by the next-generation sequencing has revealed that 7% of cancers carry the FGFR aberrations, including gene amplifications (66%), mutations (26%), and rearrangements (8%) (7). The cancer types most commonly affected were urothelial cancer, breast cancer (BC), endometrial cancer, squamous cell lung cancer, ovarian cancer, carcinoma of unknown primary, glioma and cholangiocarcinoma.

FGFR4 is frequently overexpressed in various types of cancer. It is a highly versatile protein with more than 20 known ligands (8). Specific functions of FGFR4 in carcinogenesis still remain unknown. Whereas Falvella et al. reported downregulation of FGFR4 expression in lung adenocarcinomas (ADC) (9), Sahadevan et al. indicated that FGFR4 expression was upregulated in prostate cancer (PC) (10). The FGFR4 gene is mapped to chromosome 5 (5q35.1) and is highly polymorphic (11). Single-nucleotide polymorphisms (SNP) are the most common genetic variation, representing 90% of sequence differences with an overall frequency of 1 per 1,000 bases. A common nonsynonymous SNP at codon 388 (rs351855 G>A) located in exon 9, which resulted in the substitution of arginine for glycine (Gly388Arg), was identified in the transmembrane domain of FGFR4 receptor (12). Many researchers have reported that the FGFR4 rs351855 G>A polymorphism is involved with the development of various types of cancer, including BC (12–14), PC (15, 16), colorectal cancer (CRC) (12, 13, 17), lung cancer (LC) (18–20), hepatocellular carcinoma (HCC) (21, 22), gastric cancer (GC) (23), head and neck squamous cell carcinoma (HNSCC) (24–26), and cervical cancer (27, 28). In the last decade, several meta-analyses were conducted to find that the FGFR4 Gly388Arg polymorphism was associated with increased risk of some cancers (29–33). In addition, the FGFR4 Arg388 allele has been linked to advanced stage and more frequent lymph node (LN) metastases than the wild-type homozygote (Gly/Gly) in the cohorts of CRC (12), BC (12, 34), PC (15), and LC (18). It has also been implicated in reducing disease-free survival or overall survival in patients with BC (12, 35), HNSCC (24, 25, 36), GC (37, 38), PC (39), CRC (40), and LC (9, 41). Interestingly, Serra et al. reported that the FGFR4 Arg388 allele significantly reduced the response to everolimus, an immunosuppressant medication in patients with pancreatic neuroendocrine tumors (panNET) (42). In addition, Thussbas et al. reported that FGFR4 Arg388 was significantly associated with shorter disease-free survival or overall survival among BC patients receiving adjuvant systemic therapy (35). However, other researchers have reported contrasting results in several cancer types (43–46). There have also been many studies that failed to observe any significant contribution of the FGFR4 Gly388Arg SNP to the clinicopathological parameters or prognosis in patients with cancer (13, 14, 16, 17, 21, 23, 26, 27, 35, 47–65). Therefore, the prognostic impact of the FGFR4 Gly388Arg polymorphism in cancer patients still remains controversial.

In 2010, Frullanti et al. conducted a meta-analysis of 21 studies to evaluate the role of the FGFR4 Gly388Arg polymorphism as a prognostic factor in cancers. They found a statistically significant association of the FGFR4 Arg388 allele and overall survival (hazard ratio (HR) = 1.21, 95% confidence interval (CI) 1.05 – 1.40) and LN involvement (odds ratio (OR) = 1.33, 95% CI 1.01-1.74) (66). Because of a limited number of eligible articles, however, they only included three or less studies in the subgroup analysis according to the primary tumor type. Given the amount of accumulated data thereafter, an updated quantitative synthesis has been deemed worthy. Herein, we performed this meta-analysis to evaluate the clinicopathological and prognostic impacts of the FGFR4 Gly388Arg polymorphism in patients with cancer.

The FGFR4 Gly388Arg polymorphism results in the replacement of the glycine residue with a charged arginine residue in the transmembrane domain of the receptor, which consequently exposes proximal STAT3 binding site and then enhances STAT3 signal to stimulate cell proliferation (71). Thus, the FGFR4 Arg388 variants may promote tumorigenesis by enhancing cell motility, invasiveness, and proliferation. The FGFR4 gene rs351855 G>A polymorphism has been known to confer increased genetic susceptibility to cancers (29–33). Many researchers also examined the relationship between the FGFR4 gene SNP and its pathological or prognostic roles among diverse cancer types. However, the results were inconsistent. In the current meta-analysis, we evaluated the clinicopathological and prognostic significance of the FGFR4 Gly388Arg polymorphism in cancers. The study included 11,574 patients with various types of cancer from the 44 eligible articles.

In the current study, the FGFR4 Gly388Arg SNP failed to show a significant correlation with disease stage 3/4 at the time of diagnosis, regardless of the genetic models. In the homozygous model (AA vs. GG), patients with the AA genotype showed a tendency of higher rate of LN metastases than those with the GG genotype (OR = 1.21, 95% CI: 0.99-1.49, p = 0.06). In terms of survival times, patients with the GG genotype tended to show longer overall survival, compared to those with the AG (HR = 1.09, 95% CI: 0.97-1.22, p = 0.16) or those with the AA genotype (HR = 1.31, 95% CI: 0.91-1.87, p = 0.14). In the dominant model (AG/AA. vs GG), moreover, the Arg388 allele carriers showed a significantly increased hazard of worse overall survival (HR = 1.19, 95% CI: 1.05-1.35, p = 0.006) and disease-free survival (HR = 1.25, 9% CI: 1.03-1.53, p = 0.02). The previous meta-analysis in 2011 by Frullanti et al. reported that there was a significant association between the AA genotype and LN involvement (OR = 1.33, 95% CI: 1.01-1.74, p = 0.04) (66). They also found that the Arg388 allele carriers showed worse prognosis compared to the homozygous carriers of the common Gly388 allele (HR = 1.21, 95% CI: 1.05-1.40, p = 0.01) (66). These results indicate that the FGFR4 Gly388Arg polymorphism is a potential genetic marker associated with worse prognosis in cancer patients.

The association of the FGFR4 Arg388 polymorphism with the susceptibility to cancer has mainly been described in PC and BC (15, 16, 29–31, 33). In the meta-analysis of 27 studies comprising 8,682 cases by Xiong et al., interestingly, the FGFR4 rs351855 G>A polymorphism increased the risk of PC and BC, but decreased the susceptibility of LC (33). This finding indicates that the FGFR4 Arg388 SNP might has opposite effects on different types of cancer, suggesting that this polymorphism may modify cancer susceptibility in a tissue specific manner. Therefore, the prognostic role of the FGFR4 Arg388 polymorphism may also be different among different types of cancer. In our subgroup analyses using two most common primary sites, however, there was no significant overall survival difference between the GG and AG/AA genotypes in both HNSCC (HR = 1.10, 95% CI: 0.78-1.54, p=0.65) and LC (HR = 1.16, 95% CI: 0.96-1.42, p = 0.13). In HNSCC, various tumor locations among studies may explain the negative result on the prognostic value of the FGFR4 Arg388 SNP, since different anatomical locations show different clinical and molecular characteristics (72). In terms of LC, the prognostic impact of the FGFR4 Arg388 variant may be different among histologic subtypes. Indeed, the prognostic role of this SNP was more frequently observed in patients with ADC (9, 18). In the current study, unfortunately, we could not perform the subgroup analysis according to the tumor location in HNSCC and histologic subtype in LC due to a limited number of relevant articles.

The previous studies have reported that there is significantly different in the prevalence of the FGFR4 Arg388 allele between Asians (37.2-40.1%) and Caucasians (29.5–30.4%) (29, 33). The higher frequency of the Arg388 allele in Asian populations might lead to a higher statistical power of studies in Asians than in non-Asians. However, the meta-analysis by Xu at al. reported that the association between Arg variant genotype and increase risk of cancer was significant only in Asians, not in Caucacians or Africans (33). In another meta-analysis by Liwei et al., the significant association between Arg variant genotype and susceptibility of PC was observed among European ethic descents, not among African-Americans (31). When we stratified by the ethnicity in the current study, the FGFR4 Arg388 allele was associated with worse overall survival in Asian population (HR = 1.37, 95% CI: 1.19-1.57, p < 0.00001), but not in non-Asians (HR = 1.07, 95% CI: 0.89-1.27, p = 0.47). These findings suggest that the genetic effect of the FGFR4 Gly388Arg SNP may be different among the ethnicities.

Beside the FGFR4 rs351855 G>A polymorphism, there are also other SNPs or mutations of FGFR4 which may affect the risk of cancer development or prognosis of cancer patients. The recent meta-analysis by Moazeni-Roodi et al. revealed that the FGFR4 rs1966265 C>T polymorphism significantly reduced the risk of cancer in the recessive model (TT vs CT+CC) and the rs7708357 G>A variant was significantly associated with increased cancer development in the dominant model (AG+AA vs GG) (32). The Y367C FGFR4 mutation in the extracellular juxtamembrane domain promotes the FGFR4 dimerization on the cell surface and thereby leads to ligand-independent activation of downstream signaling pathways (73). In addition, the mutations in FGFR4 kinase domain such as N535K and V550E cause receptor autophospholyation and then activate the STAT3 signal pathway (73). Some FGFR4 mutations (N535K, V548M and V550L) were reported to be relatively resistant to tyrosine kinase inhibitors (74). However, the clinical and pathological significance of these genetic variations involving FGFR4 are still needed to be investigated in further studies.

There were some inherent limitations of this meta-analysis. First, there might be a selection bias since we were only able to acquire data from published articles written in English. Second, most studies were performed retrospectively and therefore, may carry the biases of the retrospective design. Third, considerable number of included studies had a relatively small sample size, and most studies utilized univariate statistical method to compare survival outcomes. Forth, because of a paucity of relevant articles, we could not perform the subgroup analyses in other types of cancers than HNSCC and LC. Finally, there was a substantial heterogeneity in the pooled outcomes, which might weaken reliability of the meta-analysis although the random-effects model was adopted.

In conclusion, this meta-analysis elucidated that FGFR4 Gly388Arg polymorphism was associated with worse prognosis in cancer patients. Our results suggest that this SNP may be a valuable genetic marker to identify patients at higher risk of recurrence or mortality. Considering the limitations of the current study, however, large prospective researches with genotyping of the whole FGFR4 locus are warranted to reveal the clinicopathological and prognostic roles of the FGFR4 Gly388Arg SNP among various types of cancer, histology, and ethnicity.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

JHK and HSK conceived and designed the study. STP and SYJ searched the literatures and extracted the data. HSK and STP carried out the statistical analyses and data interpretation. JHK and HJJ wrote the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government, Ministry of Science and ICT (MSIT) (NRF- 2020R1G1A1005483).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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