title: PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib.
abstract: Recently, germline and somatic heterozygous mutations in the platelet-derived growth factor receptor β (PDGFRB) have been associated with familial infantile myofibromatosis (IM), which is characterized by soft tissue tumors, and overgrowth syndrome, a disease that predisposes to cancer. These mutations have not been functionally characterized. In the present study, the activity of three PDGFRB mutants associated with familial IM (R561C, P660T and N666K) and one PDGFRB mutant found in patients with overgrowth syndrome (P584R) was tested in various models. The P660T mutant showed no difference with the wild-type receptor, suggesting that it might represent a polymorphic variant unrelated to the disease. By contrast, the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents. In particular, the germline mutant identified in overgrowth syndrome, P584R, was a stronger oncogene than the germline R561C mutant associated with myofibromatosis. The distinct phenotypes associated with these two mutations could be related to this difference of potency. Importantly, all activated mutants were sensitive to tyrosine kinase inhibitors such as imatinib, nilotinib and ponatinib. In conclusion, the PDGFRB mutations previously identified in familial IM and overgrowth syndrome activate the receptor in the absence of ligand, supporting the hypothesis that these mutations cause the diseases. Moreover, imatinib seems to be a promising treatment for patients carrying these mutations. To our knowledge, these are the first confirmed gain-of-function point mutations of PDGFRB in human cancer.
authors.affiliation: De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: F A
authors.initials: FA
authors.lastname: Arts
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Chand
authors.affiliation: De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.|Ludwig Institute for Cancer Research, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Pecquet
authors.affiliation: De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: A I
authors.initials: AI
authors.lastname: Velghe
authors.affiliation: De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.|Ludwig Institute for Cancer Research, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Constantinescu
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Hallberg
authors.affiliation: De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: J-B
authors.initials: JB
authors.lastname: Demoulin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018224:Myofibromatosis / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta