Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

Medientyp: E-Artikel
Titel: Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
Beteiligte: Keck, Michaela-Kristina; Sill, Martin; Wittmann, Andrea; Joshi, Piyush; Stichel, Damian; Beck, Pengbo; Okonechnikow, Konstantin; Sievers, Philipp; Wefers, Annika K.; Roncaroli, Federico; Avula, Shivaram; McCabe, Martin G.; Hayden, James T.; Wesseling, Pieter; Øra, Ingrid; Nistér, Monica; Kranendonk, Mariëtte E. G.; Tops, Bastiaan B. J.; Zapotocky, Michal; Zamecnik, Josef; Vasiljevic, Alexandre; Fenouil, Tanguy; Meyronet, David; von Hoff, Katja; [...]
Erschienen: Springer Science and Business Media LLC, 2023
Erschienen in: Acta Neuropathologica
Sprache: Englisch
DOI: 10.1007/s00401-022-02516-2
ISSN: 0001-6322; 1432-0533
Schlagwörter: Cellular and Molecular Neuroscience ; Neurology (clinical) ; Pathology and Forensic Medicine
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either <jats:italic>PLAGL1</jats:italic> or <jats:italic>PLAGL2</jats:italic>, 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 <jats:italic>RET</jats:italic> and <jats:italic>CYP2W1</jats:italic>, 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 <jats:italic>PLAGL1</jats:italic> amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with <jats:italic>PLAGL2</jats:italic> amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for <jats:italic>PLAGL1</jats:italic>-amplified tumors, 25% for <jats:italic>PLAGL2</jats:italic>-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 <jats:italic>PLAGL1/2</jats:italic> amplification that occurs predominantly in infants and toddlers (<jats:italic>PLAGL2</jats:italic>) or adolescents (<jats:italic>PLAGL1</jats:italic>) 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.</jats:p>

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