Project description:The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

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).

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.

Dataset Information

Treatment of Pineal Region Rosette-Forming Glioneuronal Tumors (RGNT).

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Treatment of Pineal Region Rosette-Forming Glioneuronal Tumors (RGNT).

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