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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 PDGFR? 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 PDGFR? 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.

SUBMITTER: Hassan M

PROVIDER: S-EPMC6824247 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Hassan Mohammed M Butler Erin E Wilson Raphael R Roy Angshumoy A Zheng Yanbin Y Liem Priscilla P Rakheja Dinesh D Pavlick Dean D Young Lauren L LL Rosenzweig Mark M Erlich Rachel R Ali Siraj M SM Leavey Patrick J PJ Parsons D Williams DW Skapek Stephen X SX Laetsch Theodore W TW

Cold Spring Harbor molecular case studies 20191023 5

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</ ...[more]

PMID: 31645346

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Project description:PurposeTo investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis.DesignCase series with genetic and functional in vitro analyses.ParticipantsFour individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated.MethodsExome-based panel sequencing for platelet-derived growth factor receptor beta gene (PDGFRB) and notch homolog protein 3 gene (NOTCH3) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot.Main outcome measuresSequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis.ResultsWe identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and β-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria.ConclusionsWe describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Project description:ImportanceMyofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease.ObjectiveTo 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 relevanceGain-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.

Dataset Information

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

Publications

Novel <i>PDGFRB</i> rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib.

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