Article ; Online: PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis.
2017 Volume 26, Issue 10, Page(s) 1801–1810
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation ; Myofibromatosis/congenital ; Myofibromatosis/genetics ; Myofibromatosis/metabolism ; Receptor, Platelet-Derived Growth Factor beta/genetics ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptor, TIE-2/genetics |
| Chemical Substances | PDGFRB protein, human (EC 2.7.10.1) ; Receptor, Platelet-Derived Growth Factor beta (EC 2.7.10.1) ; Receptor, TIE-2 (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2017-05-15 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 1108742-0 |
| ISSN | 1460-2083 ; 0964-6906 |
| ISSN (online) | 1460-2083 |
| ISSN | 0964-6906 |
| DOI | 10.1093/hmg/ddx081 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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