Differential effects of polymorphic alleles of FGF receptor 4 on colon cancer growth and metastasis.

A gly 388 arg polymorphism (rs351855) in the transmembrane domain of the fibroblast growth factor receptor ( FGFR4 ) is associated with increased risk, staging, and metastasis in several different types of cancer. To specifically assess the impact of the polymorphic FGFR4 in colorectal cancer (CRC), we engineered CRC cell lines with distinct endogenous expression patterns to overexpress either the FGFR4 gly or FGFR4 arg alleles. The biologic analyses revealed an oncogenic importance for both polymorphic alleles, but FGFR4 gly was the stronger inducer of tumor growth, whereas FGFR4 arg was the stronger inducer of migration. An evaluation of clinical specimens revealed that FGFR4 was upregulated in 20/71 patients independent of gly 388 arg status. There was no correlation between the presence of an FGFR4 arg allele and CRC or polyp risk in 3,471 participants of the CORSA study. However, among 182 patients with CRC, FGFR4 arg -carriers had a fivefold higher risk of tumors that were stage II or greater. Together, our results established that both allelic forms of FGFR4 exert an oncogenic impact and may serve equally well as therapeutic targets in CRC. One important implication of our findings is that FGFR4 arg -carriers are at a higher risk for more aggressive tumors and therefore may profit from early detection measures. Cancer Res; 72(22); 5767–77. ©2012 AACR .