title: Differential effects of polymorphic alleles of FGF receptor 4 on colon cancer growth and metastasis.
abstract: 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.
authors.affiliation: Department of Medicine 1, Institute of Cancer Research, Clinical Institute of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Heinzle
authors.forename: Andrea
authors.initials: A
authors.lastname: Gsur
authors.forename: Monika
authors.initials: M
authors.lastname: Hunjadi
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Erdem
authors.forename: Christine
authors.initials: C
authors.lastname: Gauglhofer
authors.forename: Stefan
authors.initials: S
authors.lastname: Stättner
authors.forename: Josef
authors.initials: J
authors.lastname: Karner
authors.forename: Martin
authors.initials: M
authors.lastname: Klimpfinger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.forename: Andrea
authors.initials: A
authors.lastname: Reti
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.forename: Andreas
authors.initials: A
authors.lastname: Baierl
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018938:Caco-2 Cells; D048708:Cell Growth Processes / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055785:Gene Knockdown Techniques; D005838:Genotype; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4