Arts Florence A, Sciot Raf, Brichard Bénédicte, Renard Marleen, de Rocca Serra Audrey, Dachy Guillaume, Noël Laura A, Velghe Amélie I, Galant Christine, Debiec-Rychter Maria, Van Damme An, Vikkula Miikka, Helaers Raphaël, Limaye Nisha, Poirel Hélène A, Demoulin Jean-Baptiste
de Duve Institute, Université Catholique de Louvain, Brussels BE-1200, Belgium.
Department of Pathology, University Hospitals Leuven and KU Leuven, Leuven BE-3000, Belgium.
Hum Mol Genet. 2017 May 15;26(10):1801-1810. doi: 10.1093/hmg/ddx081.
Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma. Two patients had the same mutation in multiple separated lesions. By contrast, a third patient had three different PDGFRB mutations in the three nodules analyzed. Mutations were located in the transmembrane, juxtamembrane and kinase domains of the receptor. We showed that these mutations activated receptor signaling in the absence of ligand and transformed fibroblasts. In one case, a weakly-activating germline variant was associated with a stronger somatic mutation, suggesting a two-hit model for familial myofibromatosis. Furthermore, the mutant receptors were sensitive to the tyrosine kinase inhibitor imatinib, except D850V, which was inhibited by dasatinib and ponatinib, suggesting a targeted therapy for severe myofibromatosis. In conclusion, we identified gain-of-function PDGFRB mutations in the majority of multifocal infantile myofibromatosis cases, shedding light on the mechanism of disease development, which is reminiscent of multifocal venous malformations induced by TIE2 mutations. Our results provide a genetic test to facilitate diagnosis, and preclinical data for development of molecular therapies.
婴儿肌纤维瘤病是婴幼儿期最常见的软组织肿瘤之一。伴有内脏病变的多灶性结节预后不良。少数家族性病例与包括血小板衍生生长因子受体β（PDGFRB）在内的多种基因突变有关。在本研究中，我们对16例肌纤维瘤病或孤立性肌纤维瘤患者的编码受体酪氨酸激酶的PDGFRB进行了测序。在8例散发性多中心型疾病患者中有6例以及8例孤立性肌纤维瘤患者中有1例在PDGFRB编码序列中发现了突变。2例患者在多个分离的病变中存在相同的突变。相比之下，第3例患者在分析的3个结节中有3种不同的PDGFRB突变。突变位于受体的跨膜、近膜和激酶结构域。我们发现这些突变在无配体的情况下激活受体信号并使成纤维细胞发生转化。在1例病例中，一个弱激活的种系变异与一个更强的体细胞突变相关，提示家族性肌纤维瘤病的双打击模型。此外，除D850V外，突变受体对酪氨酸激酶抑制剂伊马替尼敏感，D850V可被达沙替尼和波纳替尼抑制，提示对严重肌纤维瘤病有靶向治疗方法。总之，我们在大多数多灶性婴儿肌纤维瘤病病例中鉴定出功能获得性PDGFRB突变，阐明了疾病发展机制，这让人联想到由TIE2突变诱导的多灶性静脉畸形。我们的结果提供了一种有助于诊断的基因检测方法，以及分子治疗开发的临床前数据。
