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

TY - JOUR

T1 - Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

AU - Keck, Michaela-Kristina

AU - Sill, Martin

AU - Wittmann, Andrea

AU - Joshi, Piyush

AU - Stichel, Damian

AU - Beck, Pengbo

AU - Okonechnikow, Konstantin

AU - Sievers, Philipp

AU - Wefers, Annika K

AU - Roncaroli, Federico

AU - Avula, Shivaram

AU - McCabe, Martin G

AU - Hayden, James T

AU - Wesseling, Pieter

AU - Øra, Ingrid

AU - Nistér, Monica

AU - Kranendonk, Mariëtte E G

AU - Tops, Bastiaan B J

AU - Zapotocky, Michal

AU - Zamecnik, Josef

AU - Vasiljevic, Alexandre

AU - Fenouil, Tanguy

AU - Meyronet, David

AU - von Hoff, Katja

AU - Schüller, Ulrich

AU - Loiseau, Hugues

AU - Figarella-Branger, Dominique

AU - Kramm, Christof M

AU - Sturm, Dominik

AU - Scheie, David

AU - Rauramaa, Tuomas

AU - Pesola, Jouni

AU - Gojo, Johannes

AU - Haberler, Christine

AU - Brandner, Sebastian

AU - Jacques, Tom

AU - Sexton Oates, Alexandra

AU - Saffery, Richard

AU - Koscielniak, Ewa

AU - Baker, Suzanne J

AU - Yip, Stephen

AU - Snuderl, Matija

AU - Ud Din, Nasir

AU - Samuel, David

AU - Schramm, Kathrin

AU - Blattner-Johnson, Mirjam

AU - Selt, Florian

AU - Ecker, Jonas

AU - Milde, Till

AU - von Deimling, Andreas

AU - Korshunov, Andrey

AU - Perry, Arie

AU - Pfister, Stefan M

AU - Sahm, Felix

AU - Solomon, David A

AU - Jones, David T W

N1 - © 2022. The Author(s).

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

U2 - 10.1007/s00401-022-02516-2

DO - 10.1007/s00401-022-02516-2

M3 - SCORING: Journal article

C2 - 36437415

VL - 145

SP - 49

EP - 69

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 1

ER -