Association of PDGFRB Mutations With Pediatric Myofibroma and Myofibromatosis

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 PARTICIPANTSIn 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 MEASURESFrequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally. RESULTSOf 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.

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas

“…Our results show that odontogenic myxoma does not share the same recurrent driver mutation of soft tissue and intra‐osseous myofibroma. Their distinct molecular pathogenesis is in line with other clinical disparities, such as the single occurrence of odontogemic myxoma, in contrast to multicentric lesions reported in some patients with myofibroma . Our data also do not support the hypothesis that the myofibroma of gnathic bones and odontogenic myxoma represent different spectra of the same entity.…”

“…These genetic alterations were detected not only in the soft tissue tumors, but also in the intra-osseous lesions (Table 1). 16,19,[28][29][30] Herein, we did not detect such mutations in any of the 15 odontogenic myxoma samples evaluated, suggesting that these PDGFRB mutations do not play a role in its tumorigenesis.…”

“…Agaimy et al reported PDGFRB somatic mutations as molecular driver events in the majority of sporadic infantile and adult solitary myofibromas (75% and 69%, respectively). These genetic alterations were detected not only in the soft tissue tumors, but also in the intra‐osseous lesions (Table ) . Herein, we did not detect such mutations in any of the 15 odontogenic myxoma samples evaluated, suggesting that these PDGFRB mutations do not play a role in its tumorigenesis.…”

“…Platelet‐derived growth factor receptor beta (PDGFRB) is a mitogen for cells of mesenchymal origin, including smooth muscle cells . Recently, PDGFRB mutations were reported in myofibromas and myofibromatosis . Recurrent driver events are yet to be reported in odontogenic myxoma .…”

“…12 Recently, PDGFRB mutations were reported in myofibromas and myofibromatosis. [13][14][15][16][17][18][19] Recurrent driver events are yet to be reported in odontogenic myxoma. [20][21][22][23] Considering that the odontogenic myxoma cells can show myofibroblastic differentiation 3,4 and myxoid areas are eventually present in myofibroma, 24,25 we raised the hypothesis whether these tumors share a common molecular profile.…”