Guillaume Dachy1, Ronald R de Krijger2, Sylvie Fraitag3, Ivan Théate4, Bénédicte Brichard5, Suma B Hoffman6, Louis Libbrecht7, Florence A Arts1, Pascal Brouillard8, Miikka Vikkula8,9, Nisha Limaye10, Jean-Baptiste Demoulin1. 1. Experimental Medicine Unit, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 2. Department of Pathology, Princess Maxima Centre for Pediatric Oncology and University Medical Centre, Utrecht, Netherlands. 3. Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. 4. Department of Pathology, Institut de Pathologie et de Génétique, Gosselies, Belgium. 5. Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium. 6. Department of Pediatrics, University of Maryland School of Medicine, Baltimore. 7. Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium. 8. Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 9. Walloon Excellence in Lifesciences and Biotechnology, Wallonia, Belgium. 10. Genetics of Autoimmune Disease and Cancer, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Abstract
IMPORTANCE: Myofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease. OBJECTIVE: To determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib. MAIN OUTCOMES AND MEASURES: Frequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally. RESULTS: Of the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations. CONCLUSIONS AND RELEVANCE: Gain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.
IMPORTANCE: Myofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease. OBJECTIVE: To determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib. MAIN OUTCOMES AND MEASURES: Frequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally. RESULTS: Of the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations. CONCLUSIONS AND RELEVANCE: Gain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.
Authors: Alexandre Persu; Piotr Dobrowolski; Heather L Gornik; Jeffrey W Olin; David Adlam; Michel Azizi; Pierre Boutouyrie; Rosa Maria Bruno; Marion Boulanger; Jean-Baptiste Demoulin; Santhi K Ganesh; Tomasz J Guzik; Magdalena Januszewicz; Jason C Kovacic; Mariusz Kruk; Peter de Leeuw; Bart L Loeys; Marco Pappaccogli; Melanie H A M Perik; Emmanuel Touzé; Patricia Van der Niepen; Daan J L Van Twist; Ewa Warchoł-Celińska; Aleksander Prejbisz; Andrzej Januszewicz Journal: Cardiovasc Res Date: 2022-01-07 Impact factor: 10.787