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PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib

Oncogene volume 35, pages 3239–3248 (2016)Cite this article

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Abstract

Recently, germline and somatic heterozygous mutations in the platelet-derived growth factor receptor β (PDGFRB) have been associated with familial infantile myofibromatosis (IM), which is characterized by soft tissue tumors, and overgrowth syndrome, a disease that predisposes to cancer. These mutations have not been functionally characterized. In the present study, the activity of three PDGFRB mutants associated with familial IM (R561C, P660T and N666K) and one PDGFRB mutant found in patients with overgrowth syndrome (P584R) was tested in various models. The P660T mutant showed no difference with the wild-type receptor, suggesting that it might represent a polymorphic variant unrelated to the disease. By contrast, the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents. In particular, the germline mutant identified in overgrowth syndrome, P584R, was a stronger oncogene than the germline R561C mutant associated with myofibromatosis. The distinct phenotypes associated with these two mutations could be related to this difference of potency. Importantly, all activated mutants were sensitive to tyrosine kinase inhibitors such as imatinib, nilotinib and ponatinib. In conclusion, the PDGFRB mutations previously identified in familial IM and overgrowth syndrome activate the receptor in the absence of ligand, supporting the hypothesis that these mutations cause the diseases. Moreover, imatinib seems to be a promising treatment for patients carrying these mutations. To our knowledge, these are the first confirmed gain-of-function point mutations of PDGFRB in human cancer.

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Acknowledgements

We would like to thank Nicolas Dauguet for cell sorting, and Anabelle Decottignies, Guy Warnier and Laure Dumoutier for generous donation of reagents. We are grateful to Ahmed Essaghir for statistical analysis. FAA is the recipient of a fellowship from FRS-FNRS – Télévie (grant number 7.4501.13 F).

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Authors and Affiliations

  1. De Duve Institute, Université Catholique de Louvain, Brussels, Belgium

    F A Arts, C Pecquet, A I Velghe, S Constantinescu & J-B Demoulin

  2. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden

    D Chand & B Hallberg

  3. Department of Molecular Biology, Umeå University, Umeå, Sweden

    D Chand

  4. Ludwig Institute for Cancer Research, Brussels, Belgium

    C Pecquet & S Constantinescu

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  1. F A Arts
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Correspondence to J-B Demoulin.

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Arts, F., Chand, D., Pecquet, C. et al. PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene 35, 3239–3248 (2016). https://doi.org/10.1038/onc.2015.383

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