PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis
| Autor: | Maria Debiec-Rychter, Bénédicte Brichard, Ann Van Damme, Raf Sciot, Amélie I. Velghe, Miikka Vikkula, Florence A. Arts, Guillaume Dachy, Christine Galant, Hélène Poirel, Laura A. Noël, Raphaël Helaers, Nisha Limaye, Marleen Renard, Audrey de Rocca Serra, Jean-Baptiste Demoulin |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Myofibroma Infantile myofibromatosis PDGFRB medicine.disease_cause Receptor tyrosine kinase Myofibromatosis Receptor Platelet-Derived Growth Factor beta 03 medical and health sciences 0302 clinical medicine Germline mutation Genetics medicine Humans Child Molecular Biology Genetics (clinical) Mutation biology Infant Newborn Infant General Medicine medicine.disease Receptor TIE-2 Dasatinib 030104 developmental biology Child Preschool 030220 oncology & carcinogenesis Cancer research biology.protein Female medicine.drug |
| Zdroj: | Human Molecular Genetics. 26:1801-1810 |
| ISSN: | 1460-2083 0964-6906 1801-1810 |
| Popis: | 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. ispartof: Human Molecular Genetics vol:26 issue:10 pages:1801-1810 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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