A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib.

Autor:	Boulouadnine B; De Duve Institute, University of Louvain, Brussels, Belgium., Filser M; Department of Genetics, Institut Curie, Paris, France., Leducq C; De Duve Institute, University of Louvain, Brussels, Belgium., Losole T; Department of Pediatric Hematology/Oncology, University of Nebraska Medical Center, Children's Nebraska, Omaha, NE., Bies J; Department of Pediatric Hematology/Oncology, University of Nebraska Medical Center, Children's Nebraska, Omaha, NE., Smetsers S; Princess Maxima Center for pediatric oncology, Utrecht, The Netherlands., Kouwenberg D; Princess Maxima Center for pediatric oncology, Utrecht, The Netherlands., de Lange I; Department of Genetics, University Medical Center Utrecht, Utrecht University, The Netherlands., Mensenkamp A; Diagnostic laboratory of the Radboud University Medical Center, Nijmegen, The Netherlands., Kordes UR; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Minard-Colin V; Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France., Orbach D; SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut Curie, Paris, France., Brichard B; Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium., de Krijger R; Princess Maxima Center for pediatric oncology, Utrecht, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands., Masliah-Planchon J; Department of Genetics, Institut Curie, Paris, France., Demoulin JB; De Duve Institute, University of Louvain, Brussels, Belgium. Electronic address: jb.demoulin@uclouvain.be.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Nov 21; Vol. 27 (2), pp. 101334. Date of Electronic Publication: 2024 Nov 21.
DOI:	10.1016/j.gim.2024.101334
Abstrakt:	Purpose: 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 (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives. Methods: We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays. Results: All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 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, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement. Conclusion: This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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