Myxoid glioneuronal tumor, PDGFRA p.K385L-mutant, arising in midbrain tectum with multifocal CSF dissemination.
Ontology highlight
ABSTRACT:
SUBMITTER: Kleinschmidt-DeMasters BK
PROVIDER: S-EPMC8713525 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
| S-EPMC7780370 | biostudies-literature
Project description:Myxoid glioneuronal tumors (MGNT) are low-grade glioneuronal neoplasms composed of oligodendrocyte-like cells in a mucin-rich stroma. These tumors feature a unique dinucleotide change at codon 385 in the platelet-derived growth factor receptor α (encoded by the PDGFRA gene), resulting in the substitution of lysine 385 into leucine or isoleucine. The functional consequences of these mutations remain largely unexplored. Here, we demonstrated their oncogenic potential in fibroblast and Ba/F3 transformation assays. We showed that the K385I and K385L mutants activate STAT and AKT signaling in the absence of ligand. Co-immunoprecipitations and BRET experiments suggested that the mutations stabilized the active dimeric conformation of the receptor, pointing to a new mechanism of oncogenic PDGF receptor activation. Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Finally, K385 substitution into another hydrophobic amino acid also activated the receptor. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.
| S-EPMC10965988 | biostudies-literature
Project description: Not available
| S-EPMC7787982 | biostudies-literature
Project description:Rosette-forming glioneuronal tumor (RGNT) of the IV ventricle is a rare and recently recognized brain tumor entity. It is histologically composed by two distinct features: a glial component, resembling pilocytic astrocytoma, and a component forming neurocytic rosettes and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in the spinal cord. Following an immunohistochemistry validation, we further performed an extensive genomic analysis, using array-CGH (aCGH), whole exome and cancer-related hotspot sequencing, in order to better understand its underlying biology. We observed the loss of 1p and gain of 1q, as well as gain of the whole chromosomes 7, 9 and 16. Local amplifications in 9q34.2 and 19p13.3 (encompassing the gene SBNO2) were identified. Moreover, we observed focal gains/losses in several chromosomes. Additionally, on chromosome 7, we identified the presence of the KIAA1549:BRAF gene fusion, which was further validated by RT-PCR and FISH. Across all mutational analyses, we detected and validated the somatic mutations of the genes MLL2, CNNM3, PCDHGC4 and SCN1A. Our comprehensive molecular profiling of this RGNT suggests that MAPK pathway and methylome changes, driven by KIAA1549:BRAF fusion and MLL2 mutation, respectively, could be associated with the development of this rare tumor entity.
| S-EPMC4570813 | biostudies-literature
Project description:A rosette-forming glioneuronal tumor (RGNT) is a rare and slow-growing central nervous system tumor. This tumor is usually assessed by MRI during the follow-up period. RGNT can show alteration of contrast enhancement regardless of tumor growth. Here, we report a case of RGNT arising from pons which shows partial enhancement on initial MRI, smaller enhancement on follow-up MRI at 10 months, and totally disappeared at 18 months without any therapy.
| S-EPMC6535692 | biostudies-literature
Project description:Rosette-forming glioneuronal tumour (RGNT) of the IV ventricle is a very recent entity, recognized in the latest WHO classification of Central Nervous System Tumors. It is composed by two distinct features: a glial component, with typical characteristics of pilocytic astrocytoma, and a component forming neurocytic rosettes, with eosinophilic regions positive for synaptofisin and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in a peculiar location, namely the spinal cord. We further performed an extensive immunohistochemistry and molecular analysis, using array-CGH (aCGH), whole exome and cancer-related hotspot sequencing, in order to better understand its underlying biology. The histology revealed a WHO grade I RGNT typically found in the fourth-ventricle. Immunoreactivity for synaptophysin and neurofilament protein was noted in the neurocytic component, whereas the glial component exhibited positivity for GFAP and S-100. Neurocytic component was found negative for GFAP. Mitoses were rare, and there was no necrosis present. Across all mutational analyses, there were detected somatic mutations in 4 genes: MLL2, CNNM3, PCDHGC4 and SCN1A. The tumor exhibited a microsatellite stable (MSS) phenotype. Array-CGH (aCGH) showed loss in 1p and gain of 1q, as well as gain of the whole chromosomes 7, 9 and 16. Moreover, we observed focal gains/losses in the chromosomes 1, 2, 3, 6, 7, 11, 14, 17, 22 and 23. Local amplifications in 9q34.2 (region with no genes mapped) and 19p13.3 (region encompassing the gene SBNO2) were identified. Additionally, we verified the KIAA1549-BRAF fusion, typically found in pilocytic astrocytomas, through aCGH, RT-PCR and FISH. Our comprehensive molecular profiling of a RGNT case suggests the existence of a unique genetic pathway for the development of these tumors: KIAA1549-BRAF fusion is a possible driver by constitutively activating MAPK pathway, and MLL2 mutation may lead to profound changes in the methylome. Taken together, these mechanisms may increase survival and/or tumorigenic capacity of cells, leading to the development of this rare entity. Two-color Agilent 8x60K array CGH (aCGH) was performed in the rosette-forming glioneuronal tumour (CY3) and reference DNA (CY5 - DNA extracted from leucocytes of the patient).
2015-07-13 | E-GEOD-64891 | biostudies-arrayexpress
Project description:The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor-avapritinib-that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.
| S-EPMC7916155 | biostudies-literature
Project description:Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
| S-EPMC7791404 | biostudies-literature
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| S-EPMC5848506 | biostudies-literature
Project description:Rosette-forming glioneuronal tumour (RGNT) of the IV ventricle is a very recent entity, recognized in the latest WHO classification of Central Nervous System Tumors. It is composed by two distinct features: a glial component, with typical characteristics of pilocytic astrocytoma, and a component forming neurocytic rosettes, with eosinophilic regions positive for synaptofisin and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in a peculiar location, namely the spinal cord. We further performed an extensive immunohistochemistry and molecular analysis, using array-CGH (aCGH), whole exome and cancer-related hotspot sequencing, in order to better understand its underlying biology. The histology revealed a WHO grade I RGNT typically found in the fourth-ventricle. Immunoreactivity for synaptophysin and neurofilament protein was noted in the neurocytic component, whereas the glial component exhibited positivity for GFAP and S-100. Neurocytic component was found negative for GFAP. Mitoses were rare, and there was no necrosis present. Across all mutational analyses, there were detected somatic mutations in 4 genes: MLL2, CNNM3, PCDHGC4 and SCN1A. The tumor exhibited a microsatellite stable (MSS) phenotype. Array-CGH (aCGH) showed loss in 1p and gain of 1q, as well as gain of the whole chromosomes 7, 9 and 16. Moreover, we observed focal gains/losses in the chromosomes 1, 2, 3, 6, 7, 11, 14, 17, 22 and 23. Local amplifications in 9q34.2 (region with no genes mapped) and 19p13.3 (region encompassing the gene SBNO2) were identified. Additionally, we verified the KIAA1549-BRAF fusion, typically found in pilocytic astrocytomas, through aCGH, RT-PCR and FISH. Our comprehensive molecular profiling of a RGNT case suggests the existence of a unique genetic pathway for the development of these tumors: KIAA1549-BRAF fusion is a possible driver by constitutively activating MAPK pathway, and MLL2 mutation may lead to profound changes in the methylome. Taken together, these mechanisms may increase survival and/or tumorigenic capacity of cells, leading to the development of this rare entity.
2015-07-13 | GSE64891 | GEO