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Ref Type Journal Article
PMID (39580648)
Authors Boulouadnine B, Filser M, Leducq C, Losole T, Bies J, Smetsers S, Kouwenberg D, de Lange I, Mensenkamp A, Kordes UR, Minard-Colin V, Orbach D, Brichard B, de Krijger R, Masliah-Planchon J, Demoulin JB
Title A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib.
Journal Vol Issue Date Pages Journal Short Title
Genetics in medicine : official journal of the American College of Medical Genetics 2024 Nov 20 101334 Genet Med
URL
Abstract Text Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor receptor beta (PDGFRB). Here, we report a novel germline intronic PDGFRB variant, c.2905-8G>A, in six unrelated infants with multifocal myofibromatosis and their relatives.We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays.All patients had multiple skin nodules, four had bone lesions and two had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting two codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously-described variants. In four tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, two patients had received imatinib without objective response. One of them switched to dasatinib with concomitant improvement.This splice-site PDGFRB variant favors the development of myofibroma featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PDGFRB D850Y missense gain of function PDGFRB D850Y lies within the protein kinase domain of the Pdgfrb protein (UniProt.org). D850Y results in increased autophosphorylation of Pdgfrb in cultured cells (PMID: 31031011), constitutive activation in a reporter assay (PMID: 39580648), and has been associated with resistance in a reporter assay (PMID: 39580648). Y
PDGFRB K968_K969insEQ insertion loss of function - predicted PDGFRB K968_K969insEQ results in the insertion of a glutamic acid (E) and a glutamine (Q) in the cytoplasmic domain of the Pdgfrb protein between amino acids 968 and 969 (UniProt.org). K968_K969insEQ results in decreased response to Pdgf stimulation in a reporter assay and in culture (PMID: 39580648), and therefore, is predicted to lead to a loss of Pdgfrb protein function.
PDGFRB R849_D850delinsH indel gain of function - predicted PDGFRB R849_D850delinsH results in a deletion of two amino acids in the protein kinase domain of the Pdgfrb protein from amino acids 849 to 850, combined with the insertion of a histidine (H) at the same site (UniProt.org). R849_D850delinsH results in constitutive Pdgfrb activity and is associated with resistance in a reporter assay (PMID: 39580648), and therefore, is predicted to lead to a gain of Pdgfrb protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PDGFRB D850Y Advanced Solid Tumor predicted - resistant Imatinib Preclinical - Biochemical Actionable In a preclinical study, PDGFRB D850Y demonstrated resistance to inhibition of Pdgfrb activity by Gleevec (imatinib) treatment in a reporter assay in cultured cells (PMID: 39580648). 39580648
PDGFRB R849_D850delinsH Advanced Solid Tumor predicted - resistant Imatinib Preclinical - Biochemical Actionable In a preclinical study, PDGFRB R849_D850delinsH demonstrated resistance to inhibition of Pdgrb activity by Gleevec (imatinib) in a reporter assay in cultured cells (PMID: 39580648). 39580648
PDGFRB D850Y Advanced Solid Tumor predicted - sensitive Dasatinib Preclinical - Biochemical Actionable In a preclinical study, Sprycel (dasatinib) treatment inhibited Pdgfrb activity in a reporter assay in a cell line expressing PDGFRB D850Y (PMID: 39580648). 39580648
PDGFRB W566R Advanced Solid Tumor predicted - sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment inhibited Pdgfrb activity in a reporter assay in a cell line expressing PDGFRB W566R (PMID: 39580648). 39580648
PDGFRB R849_D850delinsH Advanced Solid Tumor predicted - sensitive Dasatinib Preclinical - Biochemical Actionable In a preclinical study, Sprycel (dasatinib) treatment inhibited Pdgfrb activity in a reporter assay in a cell line expressing PDGFRB R849_D850delinsH (PMID: 39580648). 39580648
PDGFRB N666K Advanced Solid Tumor sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment inhibited Pdgfrb activity in a reporter assay in a cell line expressing PDGFRB N666K (PMID: 39580648). 39580648