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To conclude, we report, for the first time, two embryonal tumors with I PLAG1 i fusions sharing clinico-radiological, histopathological, immunohistochemical, and epigenetic similarities to CNS embryonal tumors with PLAG-family amplification. Central Nervous System (CNS) embryonal tumors with PLAG-family amplification have been isolated by a distinct DNA-methylation profile [[1]]. References 1 Keck M-K, Sill M, Wittmann A, Joshi P, Stichel D, Beck P. Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. [Extracted from the article]

This immunoreactivity is also present in the tumor cells of another neuronal tumor, the MVNT [[3]], which are considered to be neuronal progenitor elements. Case #2: left temporal lobe tumor involving the white matter and the cortex (e, f) showing partial contrast enhancement in the deep part of the tumor (g) and heterogeneous diffusion (restricted in the enhancing portion, increased in the non-enhancing part) (h). All three cases were initially diagnosed as CNS neuroblastoma, I FOXR2 i -activated because of clinical (children with supratentorial tumors), morphological (ganglion-like cells and neurocytic differentiation with signs of malignancy and the co-expression of Olig2 and synaptophysin), and genetic (gain of chromosome 1q in one of our cases) overlaps [[9]]. Among them, three (21%) represent new tumor types [the diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, the myxoid glioneuronal tumor, and the multinodular and vacuolating neuronal tumor (MVNT)], illustrating the increasing characterization of this group of neoplasms [[5]]. [Extracted from the article]

1:CAS:528:DC%2BC1cXpsV2hu7k%3D. 10.1007/s00401-018-1865-4 6 Navarro RE, Golub D, Hill T, McQuinn MW, William C, Zagzag D. Pediatric midline H3K27M-mutant tumor with disseminated leptomeningeal disease and glioneuronal features: case report and literature review. Gliomas with concomitant mutations of H3K27M and I BRAF/FGFR1 i are supposed to be associated with a better prognosis than other DMG, H3K27-altered according to some publications [[7]]. Arguing for this hypothesis, a previously published monothalamic tumor classified as ganglioglioma, H3K27M- and I BRAF i V600E-mutant presented secondary leptomeningeal dissemination 7 years after the initial diagnosis [[10]]. [Extracted from the article]

FET:CREB fusions have been described in a variety of tumors from various phenotypes. Recently, these fusion transcripts were reported in intracranial tumors, variably named intracranial mesenchymal myxoid tumors or angiomatoid fibrous histiocytomas. Controversy remains concerning the terminology for these tumors. Here, we report 11 cases of central nervous system mesenchymal tumors with proven FET:CREB fusion. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor or Sarcoma Classifier (v11b4/v12.2). However, by using unsupervised t‐SNE and hierarchical clustering analyses, six of the cases constituted a distinct cluster. The remaining four tumors showed no obvious relation to any of the other referenced classes but were close to the clusters of extra‐CNS angiomatoid fibrous histiocytomas (n = 1), clear cell sarcomas (n = 1), or solitary fibrous tumors (n = 2). Our findings confirm that intracranial FET:CREB‐fused tumors do not represent a single molecular tumor entity, although most samples clustered close to each other, indicating the existence of a distinct epigenetic group that could potentially be partially masked by the low number of cases included. Further analyses are needed to characterize intracranial FET:CREB fused‐defined tumors in more detail. [ABSTRACT FROM AUTHOR]

We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1‐PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1‐PATZ1 fusion transcript. RT‐PCR followed by Sanger sequencing confirmed the EWSR1‐PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N‐terminal transcriptional activation domain of EWSR1 gene and the C‐terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB‐ZF (broad‐complex, tramtrack and bric‐à‐brac ‐zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1‐PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAFV600E negative ganglioglioma, the second a BRAFV600E negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAFV600E negative gangliogliomas were screened by FISH using EWSR1 break‐apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well‐defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1‐PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas. [ABSTRACT FROM AUTHOR]

Simple Summary: Supported by the "easy-to-use" and free DKFZ central nervous system (CNS) tumor classification web tool, DNA methylation profiling is a method changing the routine diagnostic practice in neuro-oncology. This work depicts a real-world practice experience by the French neuropathology network of incorporating DNA methylation profiling into the diagnostic process of challenging pediatric CNS tumors. After two rounds of histopathological review by neuropathology experts—including morphology, neuroimaging, immunohistochemistry, panel sequencing and FISH—62 tumors still presenting diagnostic uncertainty were selected for DNA methylation profiling. Using the DKFZ "classifier" and combining all additional information obtained from DNA methylation array, we observed significant diagnostic refinements and amendments. DNA methylation was successful in a significant number of cases (71%) despite the complex specificities of the cohort. Our study evaluates how DNA methylation testing would impact diagnosis and presents illustrative and representative cases. DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores <0.84 (74.3%). (3) CNV investigations also evidenced alterations used for diagnosis and prognostication. (4) A diagnosis was finally established for 44 tumors (71%). Our results support the use of DNA methylation for challenging pediatric tumors. We demonstrated how additional methylation-based analyses complement the classifier score to support conventional histopathological diagnosis. [ABSTRACT FROM AUTHOR]

High-grade neuroepithelial tumor with I MN1 i alteration (HGNET- I MN1 i ) is a rare, recently described central nervous system (CNS) entity with a distinct methylation profile, which was formerly part of CNS-primary neuroepithelial tumors (PNET). HGNET- I MN1 i affects children (77% of reported cases [[1]-[5]]) and are characterized by a recurrent fusion implicating the I MN1 i (meningioma 1) gene [[1]]. Children with HGNET- I MN1 i present a favourable outcome with 88.0% survival (median follow-up of 65.5 months), although 48.0% presented with tumor progression. Analysis of correlation between malignant criteria defined in astroblastoma applied to HGNET- MN1 with overall survival and progression-free survival. [Extracted from the article]