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

• DOI: 10.1007/s00401-022-02516-2
• Publication Date: 2022-11-27T21:31:58Z
• Authors: Michaela-Kristina...; Martin Sill; Andrea Wittmann; Piyush Joshi; Damian Stichel; Pengbo Beck; Konstantin Okonec...; Philipp Sievers; Annika K. Wefers; Federico Roncaroli; Shivaram Avula; Martin G. McCabe; James T. Hayden; Pieter Wesseling; Ingrid Øra; Monica Nistér; Mariëtte E. G. Kr...; Bastiaan B. J. Tops; Michal Zapotocky; Josef Zamecnik; Alexandre Vasiljevic; Tanguy Fenouil; David Meyronet; Katja von Hoff; Ulrich Schüller; Hugues Loiseau; Dominique Figarel...; Christof M. Kramm; Dominik Sturm; David Scheie; Tuomas Rauramaa; Jouni Pesola; Johannes Gojo; Christine Haberler; Sebastian Brandner; Tom Jacques; Alexandra Sexton ...; Richard Saffery; Ewa Koscielniak; Suzanne J. Baker; Stephen Yip; Matija Snuderl; Nasir Ud Din; David Samuel; Kathrin Schramm; Mirjam Blattner-J...; Florian Selt; Jonas Ecker; Till Milde; Andreas von Deimling; Andrey Korshunov; Arie Perry; Stefan M. Pfister; Felix Sahm; David A. Solomon; David T. W. Jones
• Keywords: Male; Pediatric cancer; Neuroectodermal Tumors; Central Nervous System Neoplasms/genetics; Cell Cycle Proteins; Central Nervous System Neoplasms; Neuroectodermal Tumors, Primitive/genetics; Primitive; Neuroectodermal Tumors, Primitive; Child; Wnt Signaling Pathway; Cancer; Pediatric; 0303 health sciences; RNA-Binding Proteins; 3. Good health; DNA-Binding Proteins; Child, Preschool; Female; Molecular neuro-oncology; Pediatric Cancer; Oncology and Carcinogenesis; Clinical Sciences; Transcription Factors/genetics; 610; Tumor Suppressor Proteins/genetics; 03 medical and health sciences; Rare Diseases; Clinical Research; Genetics; Humans; Wnt Signaling Pathway/genetics; Preschool; Cell Cycle Proteins/genetics; Original Paper; Neurology & Neurosurgery; Biomedical and Clinical Sciences; Tumor Suppressor Proteins; Human Genome; Neurosciences; Infant; DNA Methylation; RNA-Binding Proteins/genetics; ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre; Brain Disorders; Brain Cancer; Orphan Drug; PLAGL1; PLAGL2; DNA-Binding Proteins/genetics; Transcription Factors

AbstractPediatric 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.