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| Acta neuropathologica. 2022 Nov 27. doi: 10.1007/s00401-022-02516-2. pii: 10.1007/s00401-022-02516-2 |
| Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. |
| Keck MK1, Sill M2, Wittmann A3, Joshi P4, Stichel D5, Beck P6, Okonechnikow K7, Sievers P8, Wefers AK9, Roncaroli F10, Avula S11, McCabe MG12, Hayden JT13, Wesseling P14, Øra I15, Nistér M16, Kranendonk MEG17, Tops BBJ18, Zapotocky M19, Zamecnik J20, Vasiljevic A21, Fenouil T22, Meyronet D23, von Hoff K24, Schüller U25, Loiseau H26, Figarella-Branger D27, Kramm CM28, Sturm D29, Scheie D30, Rauramaa T31, Pesola J32, Gojo J33, Haberler C34, Brandner S35, Jacques T36, Sexton Oates A37, Saffery R38, Koscielniak E39, Baker SJ40, Yip S41, Snuderl M42, Ud Din N43, Samuel D44, Schramm K45, Blattner-Johnson M46, Selt F47, Ecker J48, Milde T49, von Deimling A50, Korshunov A51, Perry A52, Pfister SM53, Sahm F54, Solomon DA55, Jones DTW56 |
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Abstract 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. |
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© 2022. The Author(s). |
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KEYWORDS: Molecular neuro-oncology, PLAGL1, PLAGL2, Pediatric cancer |
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Publikations ID: 36437415 Quelle: öffnen |
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