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A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

ABSTRACT: Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor ? (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-? promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-? as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-? in aggressive life-threatening familial forms of the disease.

SUBMITTER: Cheung YH

PROVIDER: S-EPMC3675240 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

Cheung Yee Him YH Gayden Tenzin T Campeau Philippe M PM LeDuc Charles A CA Russo Donna D Nguyen Van-Hung VH Guo Jiancheng J Qi Ming M Guan Yanfang Y Albrecht Steffen S Moroz Brenda B Eldin Karen W KW Lu James T JT Schwartzentruber Jeremy J Malkin David D Berghuis Albert M AM Emil Sherif S Gibbs Richard A RA Burk David L DL Vanstone Megan M Lee Brendan H BH Orchard David D Boycott Kym M KM Chung Wendy K WK Jabado Nada N

American journal of human genetics 20130523 6

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 af ...[more]

PMID: 23731537

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Project description:ImportanceMyofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease.ObjectiveTo determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis.Design, setting, and participantsIn this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib.Main outcomes and measuresFrequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally.ResultsOf the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations.Conclusions and relevanceGain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.

Dataset Information

A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

Publications

A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

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