Abstract
Colorectal cancer (CRC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Fibroblast growth factor receptor 4 (FGFR4) is a receptor tyrosine kinase that has been shown to play a key role in cancer development and prognosis via the activation of its downstream oncogenic signaling pathways. The present study aimed to explore the impact of FGFR4 gene polymorphisms on the risk and progression of CRC. Three FGFR4 single-nucleotide polymorphisms (SNPs), including rs1966265, rs351855, and rs7708357, were evaluated in 413 CRC cases and 413 gender- and age-matched cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of CRC between the case and control group. However, while assessing the clinicopathological parameters, patients of rectal cancer possessing at least one minor allele of rs1966265 (AG and GG; AOR, 0.236; p = 0.046) or rs351855 (GA and AA; AOR, 0.191; p = 0.022) were found to develop less metastasis as compared to those who are homozygous for the major allele. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) revealed that rs351855 regulated FGFR4 expression in many human tissues, and increased FGFR4 levels were associated with the occurrence, advanced stage, and distal metastasis of colon adenocarcinoma. These data suggest that the amino acid change in combination with altered expression levels of FGFR4 due to genetic polymorphisms may affect CRC progression.
Highlights
Colorectal cancer (CRC) is among the most frequent malignancies worldwide [1]
We found that patients of rectal cancer who carry at least one polymorphic allele of two missense singlenucleotide polymorphisms (SNPs) (AG and GG for rs1966265; adjusted odds ratios (AORs), 0.236; 95% confidence intervals (CIs), 0.057–0.972; p = 0.046) (GA and AA for rs351855; AOR, 0.191; 95% CI, 0.046–0.786; p = 0.022) developed less distal metastasis (Table 4 and ??), yet the genetic effect was marginal as considering multiple testing
We reported that Fibroblast growth factor receptor 4 (FGFR4) gene polymorphisms, rs1966265 and rs351855, mediated the metastatic potential of CRC but did not confer the susceptibility to colorectal malignancies
Summary
Colorectal cancer (CRC) is among the most frequent malignancies worldwide [1]. Despite the current advance in surgery and other therapy options, the age-standardized mortality rate of CRC has increased over the years in Taiwan [3]. Such high incidence and death rates are largely attributed to the multifactorial nature of this neoplasm. It has been well documented that major external causes of CRC include but are not limited to diet and habitual exposure of cancer-causing substances, such as tobacco use and alcohol consumption [4]. Considering the high heterogeneity in CRC pathogenesis, all these disease risks appear to be mutually intertwined and necessary to assess the cancer prognosis
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