Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib

Abstract

Infantile myofibromatosis (IM) is an aggressive neoplasm composed of myofibroblast-like cells in children. Although typically localized, it can also present as multifocal disease, which represents a challenge for effective treatment. IM has previously been linked to activating somatic and germline point mutations in the PDGFRβ tyrosine kinase encoded by the PDGFRB gene. Clinical panel-based targeted tumor sequencing of a tumor from a newborn with multifocal IM revealed a novel PDGFRB rearrangement, which was reported as being of unclear significance. Additional sequencing of cDNA from tumor and germline DNA confirmed a complex somatic/mosaic PDGFRB rearrangement with an apparent partial tandem duplication disrupting the juxtamembrane domain. Ectopic expression of cDNA encoding the mutant form of PDGFRB markedly enhanced cell proliferation of mouse embryo fibroblasts (MEFs) compared to wild-type PDGFRB and conferred tumor-forming capacity on nontumorigenic 10T1/2 fibroblasts. The mutated protein enhanced MAPK activation and retained sensitivity to the PDGFRβ inhibitor imatinib. Our findings reveal a new mechanism by which PDGFRB can be activated in IM, suggest that therapy with tyrosine kinase inhibitors including imatinib may be beneficial, and raise the possibility that this receptor tyrosine kinase might be altered in a similar fashion in additional cases that would similarly present annotation challenges in clinical DNA sequencing analysis pipelines.

Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group

“…This is reminiscent of the pathogenic variants found in another receptor tyrosine kinase gene, TIE2, in venous malformations [17]. Finally, a complex somatic/mosaic PDGFRB re-arrangement with an apparent partial tandem duplication involving the juxtamembrane domain and resulting in MAPK activation was recently detected in a newborn with multicentric IM [18].…”

Aggressive infantile myofibromatosis with intestinal involvement

“…The p.Arg561Cys mutation presumably disrupts the inhibitory juxtamembrane domain of PDGFRb, leading to constitutive activation of its kinase domain. The Arg561 residue seems to have a key function for the juxtamembrane-kinase domain interaction and is the most frequently mutated residue in IM families [9,29]. PDGFRB mutations show incomplete penetrance and variable expressivity, indicating additional genetic modifiers.…”

Reply to comment on: Solitary myofibroma preceding the development of multicentric myofibromatosis: A report of two cases with surveillance recommendations

“…Beyond the specific points discussed in these correspondences, we take this opportunity to invite a continued dialogue to collectively share experiences of the spectrum of this disease. As demonstrated in recent publications, we anticipate that further biological insight will be critical for individualizing risk status 1‐3 …”