PDGFRB Mutations Research Articles

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas.

The molecular pathogenesis of odontogenic myxoma has not been established yet. Considering that odontogenic myxoma may show myofibroblastic differentiation and myxoid areas can be observed in intra-osseous myofibromas, we tested the hypothesis whether both tumors share a common molecular profile. As recent studies have reported PDGFRB recurrent driver mutations in myofibroma, we evaluated PDGFRB mutations in odontogenic myxomas. A convenience sample of 15 odontogenic myxomas cases was selected. We direct sequenced PDGFRB exons 12 and 14, where p.R561C (c.1681C>T) and p.N666K (c.1998C>G) hotspot mutations have been reported among others in single and/or multiple myofibromas. All 15 odontogenic myxoma samples were successfully sequenced, and all 15 had wild-type sequences for the PDGFRB mutations investigated. Our findings suggest that PDGFRB mutations do not play a role in odontogenic myxoma pathogenesis, which might be helpful in the differential diagnosis of challenging cases.

MYORG-related disease is associated with central pontine calcifications and atypical parkinsonism.

ObjectiveTo identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations.MethodsUsing next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here.ResultsWe identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases.ConclusionsThis large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.

A Mutation in PDGFRB in a Family with Infantile Myofibromatosis

A Mutation in PDGFRB in a Family with Infantile Myofibromatosis

Mechanisms of calcification in Fahr disease and exposure of potential therapeutic targets.

There is growing interest in disorders involved in ectopic mineralization. Fahr disease or idiopathic basal ganglia calcification can serve as a model for ectopic mineralization in the basal ganglia, which is fairly common in the general population. In this review, we will focus on causative gene mutations and corresponding pathophysiologic pathways in Fahr disease. Patients with Fahr disease have a variability of symptoms, such as movement disorders, psychiatric signs, and cognitive impairment, but can also be asymptomatic. Fahr disease is mostly autosomal dominant inherited, and there are mutations found in 4 causative genes. Mutations in SLC20A2 and XPR1 lead to a disrupted phosphate metabolism involving brain-specific inorganic phosphate transporters. Mutations in PDGFB and PDGFRB are associated with disrupted blood-brain barrier integrity and dysfunctional pericyte maintenance. In addition, the MYORG gene has recently been discovered to be involved in the autosomal recessive inheritance of Fahr. Knowledge about the mutations and corresponding pathways may expose therapeutic opportunities for patients with Fahr disease and vascular calcifications in the brain in general.

Unique Aberrations in Intimal Sarcoma Identified by Next-Generation Sequencing as Potential Therapy Targets.

Intimal sarcomas are rare and histologically heterogeneous tumors, commonly arising from the pulmonary arteries. They have remained challenging to treat. Few studies in the literature study the genomics of this cancer. Identifying targetable alterations is an important step in advancing the treatment of intimal sarcomas. Using data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR GENIE) database, we cataloged genetic alterations and assessed their clinical utility from thirteen patients with intimal sarcoma. Notable copy number alterations included amplification in MDM2, CDK4, PDGFRA, and NOTCH2, as well as copy number losses in CDKN2A and CDKN2B. Actionable alterations included mutations in ATM/ATR, PTCH1, and PDGFRB. Moreover, genomic rearrangement events, specifically PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions were identified. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion positive tumor and PDGFRB mutations in both fusion-positive cases. Our study suggests that PDGFRB may be relevant in the tumorigenesis process. Including genomic profiling in the management of intimal sarcoma and potential enrollment in targeted therapy trials is warranted.

Novel SRF-ICA1L Fusions in Cellular Myoid Neoplasms With Potential For Malignant Behavior.

Pericytic tumors comprise a histologic continuum of neoplasms with perivascular myoid differentiation, which includes glomus tumors, myopericytoma, myofibroma, and angioleiomyoma. Despite their morphologic overlap, recent data suggest a dichotomy in their genetic signatures, including recurrent NOTCH gene fusions in glomus tumors and PDGFRB mutations in myofibromas and myopericytomas. Moreover, SRF-RELA fusions have been described in a subset of cellular variants of myofibroma and myopericytoma showing myogenic differentiation. Triggered by an index case of an unclassified cellular myoid tumor showing a novel SRF-ICA1L fusion we have investigated our files for cases showing similar histology and screened them using a combined approach of targeted RNA sequencing and fluorescence in situ hybridization. A fusion between SRF exon 4 and ICA1L exon 10 or 11 was identified in a total of 4 spindle cell tumors with similar clinicopathologic features. Clinically, the tumors were deep-seated and originated in the trunk or proximal lower extremity of adult patients (age range: 23 to 55 y). Histologically, the tumors were composed of cellular fascicles of monomorphic eosinophilic spindle cells showing increased mitotic activity, harboring densely hyalinized stroma, often with focal areas of necrosis. All 4 tumors had similar immunoprofiles with positivity for smooth muscle actin, calponin, and smooth muscle myosin heavy chain. Tumors were negative for desmin and caldesmon, markers often seen in SRF-RELA-positive tumors with similar morphology. Follow-up information was available in 3 patients. Two patients had no evidence of disease, 2 and 5 years after surgical resection. One patient, a 35-year-old male patient with a 19 cm deep-seated tumor with brisk mitotic activity (>20 mitoses in 10 HPF), developed lung metastases 7 years after initial diagnosis. In summary, we report a series of 4 cellular myoid tumors with novel SRF-ICA1L gene fusions, characterized by bland spindle cell fascicular growth, expression of specific smooth muscle markers, elevated mitotic activity, marked stromal hyalinization, focal coagulative necrosis, and potential for malignant behavior. Given the morphologic overlap with related cellular myopericytic tumors with SRF-RELA fusions, it is likely that SRF-ICA1L fusions define a similar subset of neoplasms composed of immature smooth muscle cells.

PF548 PROGNOSTIC MUTATIONS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME TREATED WITH HEMATOPOIETIC STEM‐CELL TRANSPLANTATION

Background:Genetic mutations in MDS patients are closely related with clinical phenotypes and prognosis in MDS patients. But whether mutations are prognostic for outcomes after allogeneic hematopoietic stem‐cell transplantation(allo‐HSCT) remains to be elaborated.Aims:This research was done to figure out whether genetic mutations help the risk‐stratification in MDS patients received transplantation.Methods:Targeted mutational analysis were performed on samples obtained before transplantation from 151 patients underwent HSCT. Overall‐survival(OS) was calculated from the date of transplantation to date of death, and surviving patients were censored at the date on which they were last known to be alive. Diease‐free survival(DFS) was calculated from the time of transplantation to date of relapse or death and was censored at the last date known to alive without relapse. We analyzed the relationship of mutations and clinical outcomes. Curves for OS and DFS were generated using the Kaplan‐Meier method and compared using log‐rank test.Cumulative incidence of nonrelapse death and relapse was assessed using competing risks from time of HSCT to nonrelapse death or relapse by the Gray test.Results:All 151 patients carried more than one mutations, most frequently in DNAH2(47.02%), KDM6B(42.38%), USH2A(41.06%), KMT2D(38.41%), PCLO(33.11%), CCDC168(32.45%), U2AF1(29.14%), TET2(27.81%), ASXL1(25.83%), ARID1B(23.18%). In univariable analyses, TP53 or PPM1D mutations, ANKRD26 mutations, FLT3 abnormalities(including FLT3‐ITD), PDGFRB mutations were associated with shorter OS(TP53 or PPM1D, P = 0.064; ANKRD26, P = 0.025, FLT3 abnormalities: P = 0.046; PDGFRB, P = 0.044) and DFS(TP53 or PPM1D, P = 0.019; ANKRD26, P = 0.058, FLT3 abnormalities: P = 0.047; PDGFRB, P = 0.048). In multivariable analysis including clinical variables, monosomal karyotype status, HCT‐CI, and candidate genes, PDGFRB mutations and FLT3 abnormalities were each independently associated with shorter OS(PDGFRB mutations, HR = 2.979, P = 0.021; FLT3 abnormalities, HR = 2.677, P = 0.018) and DFS(PDGFRB mutations, HR = 2.779, P = 0.019; FLT3 abnormalities, HR = 2.288, P = 0.03). PDGFRB mutations(P = 0.042), ANKRD26 mutations (P = 0.004) were associated with higher non‐relapse mortality rate. FLT3 abnormalities was associated with higher relapse rate in RAEB patients(P = 0.004).Summary/Conclusion:PDGFR mutations and FLT3 abnormalities are independently associated with shorter survival in MDS patients treated with allo‐HSCT.

Myopericytomatosis of the Foot: a Case Report Including Molecular Identification of a PDGFRB Mutation

This case report is about myopericytomatosis, a recently described rare tumor entity with only a dozen cases found in PubMed. Histologically, this tumor is characterized by diffuse infiltration of innumerable discrete myopericytoma-like nodules composed of myoid cells in a perivascular distribution. PDGFRB mutation has been linked to myopericytomatosis as well as other myopericytic tumors. The aim of this paper is to share the clinical presentation and expand the spectrum of genetic findings. We report a case of myopericytomatosis arising around the left ankle of a 73-year-old man. MRI, biopsy, and histopathology were the main diagnostic steps. Targeted next-generation sequencing was carried out to analyze the tumor sample. We performed local excision for tumor mass reduction, as wide resection was impossible a priori based on the delicate anatomical region with important structures in close proximity. Genetic analysis revealed a missense mutation of PDGFRB. PDGFRB alteration seems to play a pathogenic role in myopericytomatosis as highlighted in previously reported cases. Currently, myopericytomatosis is best treated surgically.

A novel PDGFRB sequence variant in a family with a mild form of primary familial brain calcification: a case report and a review of the literature

BackgroundPrimary familial brain calcification is a rare autosomal dominant or recessive neurodegenerative disease, characterized by bilateral brain calcifications in different areas of the brain. It is a clinically heterogeneous disease and patients are reported to exhibit a wide spectrum of neurological and psychiatric symptoms. Mutations in five genes have been identified so far including SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG. PDGFRB encodes the platelet-derived growth factor receptor-beta, and is expressed in neurons, vascular smooth muscle cells and pericytes. Patients with a PDGFRB mutation seem to exhibit a milder phenotype and milder brain calcification on brain imaging than patients with SLC20A2 and PDGFB mutations. However, this is based on a few observations so far.Case presentationWe present a Danish family with bilateral brain calcifications and mild clinical symptoms of primary familial brain calcification, segregating with a novel PDGFRB sequence variant: c.1834G > A; p.(Gly612Arg), detected by whole exome sequencing. The variant results in physiochemical changes at the amino acid level, and affects a highly conserved nucleotide as well as amino acid. It is located in the tyrosine kinase domain of PDGFRβ. Segregation analysis and in silico analyses predicted the missense variant to be disease causing.ConclusionOur study confirms that PDGFRB mutation carriers in general have a mild clinical phenotype, and basal ganglia calcifications can be detected by a CT scan, also in asymptomatic mutation carriers.

Effects of Sunitinib and Other Kinase Inhibitors on Cells Harboring a PDGFRB Mutation Associated with Infantile Myofibromatosis.

Infantile myofibromatosis represents one of the most common proliferative fibrous tumors of infancy and childhood. More effective treatment is needed for drug-resistant patients, and targeted therapy using specific protein kinase inhibitors could be a promising strategy. To date, several studies have confirmed a connection between the p.R561C mutation in gene encoding platelet-derived growth factor receptor beta (PDGFR-beta) and the development of infantile myofibromatosis. This study aimed to analyze the phosphorylation of important kinases in the NSTS-47 cell line derived from a tumor of a boy with infantile myofibromatosis who harbored the p.R561C mutation in PDGFR-beta. The second aim of this study was to investigate the effects of selected protein kinase inhibitors on cell signaling and the proliferative activity of NSTS-47 cells. We confirmed that this tumor cell line showed very high phosphorylation levels of PDGFR-beta, extracellular signal-regulated kinases (ERK) 1/2 and several other protein kinases. We also observed that PDGFR-beta phosphorylation in tumor cells is reduced by the receptor tyrosine kinase inhibitor sunitinib. In contrast, MAPK/ERK kinases (MEK) 1/2 and ERK1/2 kinases remained constitutively phosphorylated after treatment with sunitinib and other relevant protein kinase inhibitors. Our study showed that sunitinib is a very promising agent that affects the proliferation of tumor cells with a p.R561C mutation in PDGFR-beta.

PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia

AbstractPhiladelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G, which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.

Phenotype expansion and development in Kosaki overgrowth syndrome.

We expand the Kosaki overgrowth syndrome (KOGS) phenotype by over 70% to include 24 unreported KOGS symptoms, in a first male patient, the third overall associated with the PDGFRB c.1751C>G p.(Pro584Arg) mutation. Eighteen of these symptoms are unique to our patient, the remaining six are shared with other patients. Of the 24 unreported features overall, 6 show marked phenotype evolution and varying time of onset. The triangular face detected at 14 months and long palpebral fissures with lateral ectropion at 4 years are present in other members of the cohort. The remaining 4 are unique to Patient 5: pronounced macrocephaly from birth, increasingly triangular anterior skull from 14 months, camptodactyly, emerging at 4 years and worsening joint contractures from 6 years. Compilation of all new symptoms reported here with published clinical data further identifies at least 18 clinical parameters common to all cases to date, encompassing both known KOGS-associated PDGFRB mutations. We therefore propose a set of 18 core KOGS symptoms, with 16 present in early childhood. These results should also impact diagnostic/prognostic scope, intervention and outcome potential for KOGS patients, particularly for developmentally progressive conditions such as scoliosis and myofibroma.

Abstract P2-06-01: Molecular characterization of human malignant phyllodes tumors reveals potential targeted approaches

Abstract Malignant phyllodes tumor (MPT) which belong to the fibroepithelial neoplasm spectrum is a rare type of breast malignancy, and currently there is no effective targeted approach available for MPT. In this study, we tried to identify key genomic alterations and biologic pathways in MPT by whole exome and RNA sequencing of nine MPT tissues. Whole exome sequencing revealed somatic alterations in EGFR, MED12, PIK3CA, PIK3R1, PDGFRA, PDGFRB, PTEN, and TP53. Transcriptome sequencing showed dysregulation of ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling in MPTs when compared to normal breast or invasive breast cancer tissues. Based on the transcriptome profiles, the MPTs were classified into two subtypes; fibrous subtype with upregulation of stromal genes such as collagens and epithelial subtype with upregulation of E-cadherin and Claudins. The molecular classification of fibrous and epithelial subtypes was validated in 28 paraffin-embedded MPT tissues. The fibrous subtype showed higher mitotic index and increased risk for recurrence when compared to the epithelial subtype. We established a patient-derived xenograft model from one fibrous subtype MPT which harbored somatic mutation in PIK3R1 and PDGFRB. In that model, targeted treatment against PIK3CA/mTOR and PDGFR pathways effectively suppressed the tumor growth in vivo. Our data provide insights on the biologic understanding of MPT and suggest a clinically relevant molecular classification. Furthermore, we show that developing effective targeted approaches in MPT can be possible with genomic profiles and patient-derived xenograft models. The clinical efficacy of targeting PDGFR and PIK3CA/mTOR pathways in MPT should be tested in future clinical trials. Citation Format: Moon H-G, Yun J, Hong BS, Lee E, Lee H-B, Han W, Kim J-I, Noh D-Y, Heo W, Hur S, Kang W, Lee C. Molecular characterization of human malignant phyllodes tumors reveals potential targeted approaches [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-06-01.

Myofibroma/myofibromatosis: a clinicopathologic analysis of 9 cases

Objective: To investigate the clinical and histological features, diagnosis and differential diagnosis of myofibroma/myofibromatosis. Methods: The clinical data and pathology features of nine cases of myofibroma/myofibromatosis were collected from August 2011 to November 2016 in Affiliated Drum Tower Hospital, Nanjing University Medical School and Children's Hospital of Nanjing Medical University. Immunohistochemistry(IHC), PDGFRB molecular analysis and ETV6-NTRK3 gene fusion were performed and relevant literature reviewed. Results: There were 7 males and 2 females, with age ranging from 3 days to 18 years (mean 5 years). The tumors were located in head and neck (eight cases) and trunk (one case). Clinically, the tumors presented as freely movable nodules. Microscopically, they appeared biphasic with alternating light- and dark-staining areas. The light-staining area consisted mainly of plump myoid spindle cells with eosinophilic cytoplasm arranged in nodules, short fascicles, or whorls.The dark-staining area was composed of round or polygonal cells with slightly hyperchromatic nuclei or small spindle cells arranged around a distinct hemangiopericytoma-like vascular pattern. IHC showed the tumor cells in the light-staining area were strongly positive for vimentin and SMA, while cells in dark-staining area were strongly positive for vimentin, and weakly for SMA. Tumor cells were negative for desmin, S-100 protein, h-Caldesmon, CD34 and STAT6. Analysis of PDGFRB mutations was performed in seven cases. Two cases showed 12 exon point mutation c. 1681 c>T(p.R561C), one case showed 14 exon point mutation c. 1998C>G (p.N666K). ETV6-NTRK3 gene fusion was not detected by fluorescence in situ hybridization in four patients under three years old. All cases were followed for 6 to 68 months, with two recurrences. Conclusions: Myofibroma/myofibromatosis is an uncommon benign myofibroblastic tumor of infancy and childhood. The tumor can appear biphasic, and may show PDGFRB point mutation which is of potential diagnostic value.

Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes.

Genome-wide next-generation sequencing has revealed several driver mutations and has allowed the establishment of a molecular taxonomy of gastric cancer. However, there are few detailed studies on the mutational spectrum of poorly cohesive gastric carcinoma. Thus, this study aim to investigate its mutation profile based on clinicopathological characteristics. Herein, we analysed the mutational pattern of 77 genes in a cohort of 91 patients with poorly cohesive carcinoma by using targeted sequencing, and evaluated the clinicopathological significance of the various mutations based on histological pattern, either signet ring cell (SRC) or other types of poorly cohesive carcinoma (not otherwise specified) (PCC-NOS). Panels of seven (PIK3CA, CDH1, PTEN, RHOA, HDCA9, KRAS, and ATM), three (PIK3CA, CTNNB1, and KRAS) and two (HDCA9 and IGF1R) genes were associated with a diffuse infiltrative growth pattern, lymphovascular invasion, and perineural invasion, respectively. Furthermore, PDGFRB mutations were associated with a favourable prognosis, whereas MET mutations were associated with a poor prognosis. The PCC-NOS-predominant type was associated with a greater depth of invasion, lymph node metastasis and poorer prognosis than the SRC-predominant type. Mutations in TP53, BRAF, PI3CA, SMAD4 and RHOA were associated with PCC-NOS. Interestingly, RHOA-mutated gastric cancers showed a distinct morphology, as they were characterised by a superficial SRC or tubular component and a deep invasive PCC-NOS component with desmoplasia. Taken together, our findings demonstrate that gastric poorly cohesive carcinomas show several mutational patterns associated with specific clinicopathological characteristics, and particularly show distinct morphological findings when associated with RHOA mutation.

Clinical and radiological diversity in genetically confirmed primary familial brain calcification

Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.

Activating mutation of PDGFRB gene in a rare cardiac undifferentiated intimal sarcoma of the left atrium: a case report.

Cardiac sarcoma is a rare malignant tumor with undefined genetic mutations and no targeted therapy. Here in one rare case of undifferentiated cardiac intimal sarcoma (IS), a next-generation sequencing based assay, MSK-IMPACT (Memorial Sloan Kettering - Integrated Mutation Profiling of Actionable Cancer Targets), identified a somatic, activating mutation in PDGFRB, along with amplification of PDGFRA. This E472D mutation of PDGFRB was discovered for the first time in IS. These findings suggest that concurrent aberrant PDGFRA and PDGFRB signaling may be a diagnostic biomarker and molecular therapeutic target of IS of the heart.

STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb+/D849V mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb+/D849V mice with Stat1 knockout (Stat1-/-Pdgfrb+/D849V ) are rescued from autoinflammation and have improved life span compared with Stat1+/-Pdgfrb+/D849V mice. Furthermore, PDGFRβ-STAT1 signaling suppresses PDGFRβ itself. Thus, Stat1-/-Pdgfrb+/D849V fibroblasts exhibit increased PDGFRβ signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1+/-Pdgfrb+/D849V mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb+/D849V mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFRβ signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.

Myopericytomatosis: Clinicopathologic Analysis of 11 Cases With Molecular Identification of Recurrent PDGFRB Alterations in Myopericytomatosis and Myopericytoma.

Myopericytoma is a benign tumor of concentrically distributed perivascular myoid cells. Its molecular basis and relationship with myofibroma/myofibromatosis and other pericytic tumors are not fully understood. In our consultation/surgical files of over 1000 myopericytic lesions, we identified 11 cases with diffuse dermal/subcutaneous involvement by microscopic myopericytomatous nodules, a phenomenon we have termed myopericytomatosis. Myopericytomatosis affected mostly adults (female:male=8:3; median age, 37 y; range, 9 to 63 y) in the lower extremities (foot/ankle, 5; calf, 3; knee, 1; thigh, 1; neck, 1) over months to 25 years, ranging from 1.5 to 11.0 (median, 6.0) cm in size. Histologically, myopericytomatosis displayed diffuse infiltration by innumerable discrete myopericytoma/myofibroma-like nodules of bland spindled-to-ovoid cells (smooth muscle actin positive), in a mainly perivascular distribution. No mitoses, atypia, or necrosis was noted. All patients were treated by surgical excision (1 patient also received adjuvant radiation), with margins focally positive in 5 of 6 known cases. Of the 6 cases with follow-up of 0.2 to 13.7 (median, 3.4) years, 1 recurred locally twice, while 5 cases showed no recurrence. Targeted next-generation DNA sequencing identified PDGFRB alterations in all cases of myopericytomatosis and conventional myopericytoma tested (5 cases each), including mutations in 4 cases of myopericytomatosis (N666K in 3; Y562-R565 deletion in 1 case) and 3 myopericytomas (Y562C, K653E, and splice acceptor deletion in 1 case each), as well as low-level PDGFRB amplification in 2 cases of myopericytomatosis and 4 myopericytomas. No BRAF, NOTCH, or GLI1 alterations were detected. In summary, myopericytomatosis is a rare, strikingly diffuse, but apparently benign variant of myopericytoma that typically involves superficial soft tissue in adults with innumerable discrete microscopic myopericytomatous nodules. The strongly activating PDGFRB mutation N666K is noted in myopericytomatosis, but not in conventional myopericytoma, suggesting that PDGFRB mutation status may account for their pathogenetic differences. As PDGFRB alterations are present in myopericytoma/myopericytomatosis and infantile myofibromatosis/myofibroma, these entities indeed lie within a histogenetic continuum. Identification of PDGFRB alterations suggests tyrosine kinase inhibition as a potential therapeutic strategy in myopericytic neoplasms if needed.

Abstract 534: PDGFRB gain-of-function mutations in multifocal infantile myofibromatosis: Implications for diagnosis & therapy

Abstract Myofibromas and infantile myofibromatosis are among the most prevalent soft tissue tumors of infancy and childhood. They are characterized by the presence of solitary or multiple nodules in the skin, subcutaneous soft tissues, bones, muscles and viscera. Multifocal myofibromatosis with visceral lesions is associated with a poor prognosis. The pathogenesis of sporadic myofibromatosis is unknown. A few familial cases have been linked to mutations in various genes including PDGFRB, which encodes a receptor tyrosine kinase that is highly expressed in fibroblasts, pericytes and other cells of mesenchymal origin. In the present study, we investigated whether the sporadic form of the disease may also be associated with PDGFRB mutations. We sequenced the whole coding sequence of PDGFRB in 20 cases of myofibromatosis or solitary myofibroma using the Ion AmpliSeq technology at high coverage (Life Technologies). Six different mutations in the coding sequence of PDGFRB were identified in seven patients, six of whom had the sporadic multicentric form of the disease, with a median age at diagnosis of 13 months [range: 0 to 7 years]. Mutations were located in four different exons: the classical hotspot exons 12 and 14, encoding the juxtamembrane and the kinase domains, but also the exons 11 and 18, encoding the transmembrane domain and the activation loop respectively. The percentage of mutated reads varied between 4 and 33%, suggesting that the mutations were somatic, except for one patient who had a germline R561C substitution and a somatic second hit. Two patients had the same mutation in multiple separated lesions, suggesting an early post-zygotic mutation in a progenitor cell. By contrast, a third patient had three different PDGFRB mutations in the three nodules analyzed. We showed that these mutations constitutively activated receptor signaling in the absence of ligand and stimulated fibroblast proliferation in vitro. Furthermore, the mutant receptors were sensitive to the tyrosine kinase inhibitor imatinib, except D850V, which was inhibited by dasatinib and ponatinib, suggesting a treatment for severe myofibromatosis. In conclusion, we identified activating PDGFRB mutations in 66% of sporadic multifocal infantile myofibromatosis cases, shedding light on the mechanism of disease development. Our results provide a genetic test to facilitate diagnosis, and preclinical data for development of molecular therapies. Citation Format: Florence A. Arts, Raf Sciot, Bénédicte Brichard, Marleen Renard, Laura A. Noël, Amélie I. Velghe, Christine Galant, Maria Debiec-Rychter, An Van Damme, Miikka Vikkula, Raphaël Helaers, Nisha Limaye, Hélène A. Poirel, Jean-Baptiste B. Demoulin. PDGFRB gain-of-function mutations in multifocal infantile myofibromatosis: Implications for diagnosis & therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 534. doi:10.1158/1538-7445.AM2017-534