Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele.
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.
Bange
Johannes
J
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
Prechtl
Dieter
D
Cheburkin
Yuri
Y
Specht
Katja
K
Harbeck
Nadia
N
Schmitt
Manfred
M
Knyazeva
Tatjana
T
Müller
Susanne
S
Gärtner
Silvia
S
Sures
Irmi
I
Wang
Hongyang
H
Imyanitov
Evgeny
E
Häring
Hans-Ulrich
HU
Knayzev
Pjotr
P
Iacobelli
Stefano
S
Höfler
Heinz
H
Ullrich
Axel
A
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
D017468:Receptors, Fibroblast Growth Factor; D001120:Arginine; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4