PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis.
Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma. Two patients had the same mutation in multiple separated lesions. By contrast, a third patient had three different PDGFRB mutations in the three nodules analyzed. Mutations were located in the transmembrane, juxtamembrane and kinase domains of the receptor. We showed that these mutations activated receptor signaling in the absence of ligand and transformed fibroblasts. In one case, a weakly-activating germline variant was associated with a stronger somatic mutation, suggesting a two-hit model for familial myofibromatosis. Furthermore, the mutant receptors were sensitive to the tyrosine kinase inhibitor imatinib, except D850V, which was inhibited by dasatinib and ponatinib, suggesting a targeted therapy for severe myofibromatosis. In conclusion, we identified gain-of-function PDGFRB mutations in the majority of multifocal infantile myofibromatosis cases, shedding light on the mechanism of disease development, which is reminiscent of multifocal venous malformations induced by TIE2 mutations. Our results provide a genetic test to facilitate diagnosis, and preclinical data for development of molecular therapies.
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Florence A
FA
Arts
Department of Pathology, University Hospitals Leuven and KU Leuven, Leuven BE-3000, Belgium.
Raf
R
Sciot
Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Bénédicte
B
Brichard
Department of Pediatric Hemato-oncology, University Hospitals Leuven, Leuven BE-3000, Belgium.
Marleen
M
Renard
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Audrey
A
de Rocca Serra
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Guillaume
G
Dachy
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Laura A
LA
Noël
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Amélie I
AI
Velghe
Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels BE-1200, Belgium.
Christine
C
Galant
Department of Human Genetics, KU Leuven and University Hospitals, Leuven BE-3000, Belgium.
Maria
M
Debiec-Rychter
Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels BE-1200, Belgium.
An
A
Van Damme
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.|Walloon Excellence in Life sciences and Biotechnology (WELBIO).
Miikka
M
Vikkula
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Raphaël
R
Helaers
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Nisha
N
Limaye
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.|Center for Human Genetics, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Hélène A
HA
Poirel
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Jean-Baptiste
JB
Demoulin
D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D018224:Myofibromatosis / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics
C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D042787:Receptor, TIE-2