title: Activating somatic FGFR2 mutations in breast cancer.
abstract: It is known that FGFR2 gene variations confer a risk for breast cancer. FGFR2 and FGF10, the main ligand of FGFR2, are both overexpressed in 5-10% of breast tumors. In our study, we sequenced the most important coding regions of FGFR2 in somatic tumor tissue of 140 sporadic breast cancer patients and performed MLPA analysis to detect copy number variations in FGFR2 and FGF10. We identified one somatic heterozygous missense mutation, p.K660N (c.1980G>C), within the tyrosine kinase domain of FGFR2 in tumor tissue of a sporadic breast cancer patient, which is likely mediated by the FGFR2-IIIb isoform. The presence of wild type and mutated alleles in equal quantities suggests that the mutation has driven clonal amplification of mutant cells. We have analyzed the tyrosine kinase activity of p.K660N and another recently described somatic breast cancer mutation in FGFR2, p.R203C, after expression in HEK293 cells and demonstrated that the intrinsic tyrosine kinase activity of both mutant proteins is strongly increased resulting in elevated phosphorylation and activity of downstream effectors. To our knowledge, this is the first report of functional analysis of somatic breast cancer mutations in FGFR2 providing evidence for the activating nature of FGFR2-mediated signalling in the pathogenesis of breast cancer.
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Reintjes
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Alexandra
authors.initials: A
authors.lastname: Becker
authors.forename: Edyta
authors.initials: E
authors.lastname: Rohmann
authors.forename: Rita
authors.initials: R
authors.lastname: Schmutzler
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D056726:Genetic Association Studies; D005858:Germany; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D060885:Multiplex Polymerase Chain Reaction; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology
chemical_list: D017931:DNA Primers; C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; C496353:FGFR2 protein, human; D011505:Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2