We identified 16 HGG (11 glioblastomas, 3 anaplastic astrocytomas and 2 anaplastic gangliogliomas, 16/30, 53 %) and 1 diffuse astrocytoma harboring H3F3A K27M mutations ( Fig. 1a-e). The frequency of mutations among HGG affecting adults and children was similar (52 vs. 54 %). The mean age of adult patients with mutated tumors was lower (34 years) than that observed in patients with wild-type tumors (53 years) (Fig. 1f). All tumors affecting infants were H3F3A wild type. The distributions of mutated and wild-type HGG along the spinal cord appeared similar, but in cervical spine HGG were more frequently mutated (Fig. 1g). Neither H3F3A wild-type HGG nor DA showed immunoreactivity for mutant IDH1 R132H protein (not shown).Histones are nuclear proteins which regulate DNA replication and transcription by modifying the nucleosome structure [9]. H3.3 histone proteins, encoded by H3.3A (H3F3A) and H3.3B, are deposited on chromatin in a replication-independent manner and are enriched at actively transcribed genes and heterochromatic regions [9]. H3F3A mutations occur in a hotspot region (K27 and G34) undergoing posttranslational modifications. Similar to IDH1 mutated gliomas in adults, reduced H3.3K27 trimethylation and deregulated DNA methylation are considered to play a major role in pediatric gliomagenesis [2]. Recently, several groups have highlighted the high frequency of H3F3A K27M mutations in pediatric midline HGG as well as in DIPG [2, 3, 7, 8]. These mutations are not limited to pediatric patients, but can occur, although more rarely, in adults. H3F3A K27M mutations were frequently observed in thalamic HGG affecting young adults [1] and adult DIPG, but rare in supratentorial adult HGG [6]. Notably, the patient's age did not affect the pattern of methylation in H3F3A K27M mutant tumors [1].Diffuse high-grade gliomas (HGG) in the spinal cord are rare [5]. It is still undetermined whether they could share genetic alterations with their supratentorial counterparts: in particular, because the spinal cord has to be considered a midline structure, a high incidence of H3F3A K27M mutations could be hypothesized, as reported in diffuse pontine gliomas (DIPG) and in pediatric midline HGG [1-3, 6-8].In this study, we investigated the H3F3A K27M status of 30 primary spinal HGG affecting pediatric and adult patients.Formalin-fixed paraffin-embedded specimens of 36 primary spinal diffusely infiltrating gliomas, including 30 HGG (18 glioblastomas, WHO IV; 10 anaplastic astrocytomas, WHO III; 2 anaplastic gangliogliomas, WHO III) and 6 diffuse astrocytomas (WHO II) [5] were retrieved from the archives
Craniopharyngiomas are rare histologically benign but clinically challenging neoplasms. To obtain further information on the molecular genetics and biology of craniopharyngiomas, we analyzed a cohort of 121 adamantinomatous and 16 papillary craniopharyngiomas (ACP, PCP). We extracted DNA from formalin-fixed paraffin-embedded tissue and determined mutational status of CTNNB1, BRAF, and DDX3X by Sanger sequencing, next generation panel sequencing, and pyrosequencing. Sixteen craniopharyngiomas were further analyzed by molecular inversion profiling (MIP); 76.1% of the ACP were mutated in exon 3 of CTNNB1 encoding for β-catenin and there was a trend towards a worse event-free survival in cases mutated at Thr41. Next generation panel sequencing of 26 ACP did not detect any recurrent mutations other than CTNNB1 mutations. BRAF V600E mutations were found in 94% of the PCP, but not in ACP. GISTIC analysis of MIP data showed no significant larger chromosomal aberrations but a fraction of ACP showed recurrent focal gains of chromosomal material, other cases showed loss in the chromosomal region Xq28, and a third group and the PCP had stable genomes. In conclusion, the crucial pathogenetic event appears to be WNT activation in ACP, whereas it appears to be activation of the Ras/Raf/MEK/ERK pathway by BRAF V600E mutations in PCP.
Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/ Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC Brain Pathology 29 (2019) 205-216
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified—RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class “EP, RELA-fusion”; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
Central nervous system germinomas are characterized by a massive immune cell infiltrate. We systematically characterized these immune cells in 28 germinomas by immunophenotyping and image analysis. mRNA expression was analyzed by Nanostring technology and in situ RNA hybridization. Tumor infiltrating lymphocytes (TILs) were composed of 61.8% ± 3.1% (mean ± SE) CD3-positive T cells, including 45.2% ± 3.5% of CD4-positive T-helper cells, 23.4% ± 1.5% of CD8-positive cytotoxic T cells, 5.5% ± 0.9% of FoxP3-positive regulatory T cells, and 11.9% ±1.3% PD-1-positive TILs. B cells accounted for 35.8% ± 2.9% of TILs and plasma cells for 9.3% ± 1.6%. Tumor-associated macrophages consisted of clusters of activated PD-L1-positive macrophages and interspersed anti-inflammatory macrophages expressing CD163. Germinoma cells did not express PD-L1. Expression of genes encoding immune cell markers and cytokines was high and comparable to mRNA levels in lymph node tissue. IFNG and IL10 mRNA was detected in subfractions of TILs and in PD-L1-positive macrophages. Taken together, the strong immune reaction observed in germinomas involves inflammatory as well as various suppressive mechanisms. Expression of PD-1 and PD-L1 and infiltration of cytotoxic T cells are biomarkers predictive of response to anti-PD-1/PD-L1 therapies, constituting a rationale for possible novel treatment approaches.
Dysembryoplastic neuroepithelial tumors (DNTs) are one of the most common epilepsy-associated low-grade glioneuronal tumors of the central nervous system. Although most DNTs occur in the cerebral cortex, DNT-like tumors with unusual intraventricular or periventricular localizations have been reported. Most of them involve the septum pellucidum and the foramen of Monro. In this study, we have described the neuroradiologic, histopathologic, and molecular features of 7 cases (4 female and 3 male; patient age range, 3 to 34 y; mean age, 16.7 y). The tumors, all localized near the supratentorial midline structures in proximity to the foramen of Monro and septum pellucidum, appeared in magnetic resonance imaging as well-delimited cystic lesions with cerebrospinal fluid-like signal on T1-weighted and T2-weighted images, some of them with typical fluid-attenuated inversion recovery ring sign. Histologically, they shared features with classic cortical DNTs but did not display aspects of multinodularity. From a molecular point of view the cases investigated did not show KIAA1549-BRAF fusions or FGFR1 mutations, alterations otherwise observed in pilocytic astrocytomas, or MYB and MYBL1 alterations that have been identified in a large group of pediatric low-grade gliomas. Moreover, BRAF mutations, which so far represent the most common molecular alteration found in cortical DNTs, were absent in this group of rare periventricular tumors.
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