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.

• Authors: 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
• Journal: Cold Spring Harbor molecular case studies (Cold Spring Harb Mol Case Stud) Vol. 5 Issue 5 (10 2019) ISSN: 2373-2873 [Electronic] United States
• PMID: 31645346 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2019 Hassan et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• Protein Kinase Inhibitors
• Imatinib Mesylate
• PDGFRB protein, human
• Receptor, Platelet-Derived Growth Factor beta
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cell Line
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Fibroblasts (metabolism)
• Germ-Line Mutation (genetics)
• Humans
• Imatinib Mesylate (pharmacology)
• Infant, Newborn
• Mice
• Myofibromatosis (congenital, genetics, metabolism)
• Protein Kinase Inhibitors (therapeutic use)
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)