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

Mohammed Hassan, Erin Butler, Raphael Wilson, Angshumoy Roy, Yanbin Zheng, Priscilla Liem, Dinesh Rakheja, Dean Pavlick, Lauren L. Young, Mark Rosenzweig, Rachel Erlich, Siraj M. Ali, Patrick J. Leavey, D. Williams Parsons, Stephen X. Skapek, Theodore W. Laetsch

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalCold Spring Harbor Molecular Case Studies
Volume5
Issue number5
DOIs
StatePublished - Oct 1 2019

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Platelet-Derived Growth Factor beta Receptor
Tumors
Fibroblasts
Neoplasms
Protein-Tyrosine Kinases
Complementary DNA
Myofibroblasts
Germ-Line Mutation
DNA
Cell proliferation
Receptor Protein-Tyrosine Kinases
DNA Sequence Analysis
Point Mutation
Imatinib Mesylate
Congenital Generalized Fibromatosis
Embryonic Structures
Pipelines
Genes
Chemical activation
Cell Proliferation

Keywords

  • neoplasm of the skin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib. / Hassan, Mohammed; Butler, Erin; Wilson, Raphael; Roy, Angshumoy; Zheng, Yanbin; Liem, Priscilla; Rakheja, Dinesh; Pavlick, Dean; Young, Lauren L.; Rosenzweig, Mark; Erlich, Rachel; Ali, Siraj M.; Leavey, Patrick J.; Parsons, D. Williams; Skapek, Stephen X.; Laetsch, Theodore W.

In: Cold Spring Harbor Molecular Case Studies, Vol. 5, No. 5, 01.10.2019.

Research output: Contribution to journalArticle

Hassan, Mohammed ; Butler, Erin ; Wilson, Raphael ; Roy, Angshumoy ; Zheng, Yanbin ; Liem, Priscilla ; Rakheja, Dinesh ; Pavlick, Dean ; Young, Lauren L. ; Rosenzweig, Mark ; Erlich, Rachel ; Ali, Siraj M. ; Leavey, Patrick J. ; Parsons, D. Williams ; Skapek, Stephen X. ; Laetsch, Theodore W. / Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib. In: Cold Spring Harbor Molecular Case Studies. 2019 ; Vol. 5, No. 5.
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