title: Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.
abstract: Expression analysis of genes encoding components of the phosphotyrosine signaling system by cDNA array hybridization revealed elevated levels of FGFR4 transcripts in several mammary carcinoma cell lines. In the FGFR4 gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A conversion was discovered that results in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor. The Arg(388) allele was also found in cell lines derived from a variety of other tumor types as well as in the germ-line of cancer patients and healthy individuals. Analysis of three geographically separated groups indicated that it occurs in approximately 50% of the human population. Investigation of the clinical data of 84 breast cancer patients revealed that homo- or heterozygous carriers of the Arg(388) allele had a significantly reduced disease-free survival time (P = 0.01) within a median follow-up of 62 months. Moreover, the FGFR4 Arg(388) allele was associated with early lymph node metastasis and advanced tumor-node-metastasis (TNM) stage in 82 colon cancer patients. Consistent with this finding, MDA-MB-231 mammary tumor cells expressing FGFR4 Arg(388) exhibited increased motility relative to cells expressing the FGFR4 Gly(388) isotype. Our results support the conclusion that the FGFR4 Arg(388) allele represents a determinant that is innocuous in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bange
authors.forename: Dieter
authors.initials: D
authors.lastname: Prechtl
authors.forename: Yuri
authors.initials: Y
authors.lastname: Cheburkin
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Tatjana
authors.initials: T
authors.lastname: Knyazeva
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Silvia
authors.initials: S
authors.lastname: Gärtner
authors.forename: Irmi
authors.initials: I
authors.lastname: Sures
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Evgeny
authors.initials: E
authors.lastname: Imyanitov
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Pjotr
authors.initials: P
authors.lastname: Knayzev
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D001120:Arginine; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4