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 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.

Figure 1.. PDGFRB Mutant Distribution by Patient Age and Myofibroma Subtype

Figure 2.. PDGFRB Gain-of-Function Mutations in Myofibroma

Variants are reported according to protein location and affected exon. The activation loop is represented in white in the C-lobe of the kinase domain. Pairs of mutations identified in multiple-hits samples were p.R561C + p.N666K, p.R561C + p.N666S, p.A537D + p.I538N, p.N666K + p.W566R, p.W566R + p.Y589D, p.Y562_R565del + p.N666K, and R561_Y562delinsH + p.N666K (eTable 1 and eTable 2 in the Supplement). Variants p.K559_Y562delinsN and p.N666K were identified in 2 distinct myopericytomas from the same patient; the variants p.N666K (c.1998C>G), p.N666K (C>A), p.W566_V568delinsL, and p.Y562D were identified in 4 distinct IMF lesions from the same patient. Blue bars indicate the frequency of each variant; white circles, allele burden; green, sensitive to imatinib; red, resistant to imatinib. ECD indicates extracellular domain; IMF, infantile myofibromatosis; JMD, juxta-membrane domain; KD, kinase domain; and TMD, transmembrane domain. ^aVariants were validated by an alternative method.