Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

• Klíčová slova
• Molecular neuro-oncology, PLAGL1, PLAGL2, Pediatric cancer,
• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové supresorové proteiny genetika   MeSH
• nádory centrálního nervového systému * genetika   MeSH
• předškolní dítě MeSH
• primitivní neuroektodermové nádory * genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• proteiny vázající RNA genetika   MeSH
• signální dráha Wnt genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• nádorové supresorové proteiny MeSH
• PLAGL1 protein, human MeSH Prohlížeč
• PLAGL2 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• proteiny vázající RNA MeSH
• transkripční faktory MeSH

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

• Klíčová slova
• EP300, EWSR1, FOXO1, Gene fusion, Neuroepithelial tumor, PLAGL1, Supratentorial,
• MeSH
• dítě MeSH
• ependymom genetika   MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   MeSH
• onkogenní fúze MeSH
• proteiny buněčného cyklu genetika   MeSH
• supratentoriální nádory genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• PLAGL1 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• transkripční faktory MeSH

Paxillin (PXN) is a focal adhesion protein that has been implicated in signal transduction from the extracellular matrix. Recently, it has been shown to shuttle between the cytoplasm and the nucleus. When inside the nucleus, paxillin promotes cell proliferation. Here, we introduce paxillin as a transcriptional regulator of IGF2 and H19 genes. It does not affect the allelic expression of the two genes; rather, it regulates long-range chromosomal interactions between the IGF2 or H19 promoter and a shared distal enhancer on an active allele. Specifically, paxillin stimulates the interaction between the enhancer and the IGF2 promoter, thus activating IGF2 gene transcription, whereas it restrains the interaction between the enhancer and the H19 promoter, downregulating the H19 gene. We found that paxillin interacts with cohesin and the mediator complex, which have been shown to mediate long-range chromosomal looping. We propose that these interactions occur at the IGF2 and H19 gene cluster and are involved in the formation of loops between the IGF2 and H19 promoters and the enhancer, and thus the expression of the corresponding genes. These observations contribute to a mechanistic explanation of the role of paxillin in proliferation and fetal development.

• Klíčová slova
• Cohesin, Enhancer, H19, IGF2, Imprinting, Paxillin,
• MeSH
• buňky Hep G2 MeSH
• chromozomální proteiny, nehistonové genetika   MeSH
• extracelulární matrix genetika   MeSH
• fokální adheze genetika   MeSH
• genomový imprinting genetika   MeSH
• insulinu podobný růstový faktor II biosyntéza   genetika   MeSH
• koheziny MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• paxilin aplikace a dávkování   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• promotorové oblasti (genetika) MeSH
• proteiny buněčného cyklu genetika   MeSH
• RNA dlouhá nekódující biosyntéza   genetika   MeSH
• signální transdukce účinky léků   MeSH
• vývoj plodu genetika   MeSH
• vývojová regulace genové exprese MeSH
• zesilovače transkripce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromozomální proteiny, nehistonové MeSH
• H19 long non-coding RNA MeSH Prohlížeč
• IGF2 protein, human MeSH Prohlížeč
• insulinu podobný růstový faktor II MeSH
• paxilin MeSH
• proteiny buněčného cyklu MeSH
• RNA dlouhá nekódující MeSH