Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification - Aix-Marseille Université Access content directly
Journal Articles Acta Neuropathologica Year : 2023

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

Michaela-Kristina Keck
  • Function : Author
Martin Sill
  • Function : Author
Andrea Wittmann
  • Function : Author
Piyush Joshi
  • Function : Author
Damian Stichel
  • Function : Author
Pengbo Beck
  • Function : Author
Konstantin Okonechnikow
  • Function : Author
Philipp Sievers
  • Function : Author
Annika Wefers
  • Function : Author
Federico Roncaroli
  • Function : Author
Shivaram Avula
  • Function : Author
Martin Mccabe
  • Function : Author
James Hayden
  • Function : Author
Pieter Wesseling
  • Function : Author
Ingrid Øra
  • Function : Author
Monica Nistér
  • Function : Author
Mariëtte Kranendonk
  • Function : Author
Bastiaan Tops
  • Function : Author
Michal Zapotocky
  • Function : Author
Josef Zamecnik
  • Function : Author
Alexandre Vasiljevic
  • Function : Author
Tanguy Fenouil
  • Function : Author
David Meyronet
  • Function : Author
Katja von Hoff
  • Function : Author
Ulrich Schüller
  • Function : Author
Hugues Loiseau
  • Function : Author
Christof Kramm
  • Function : Author
Dominik Sturm
  • Function : Author
David Scheie
  • Function : Author
Tuomas Rauramaa
  • Function : Author
Jouni Pesola
  • Function : Author
Johannes Gojo
  • Function : Author
Christine Haberler
  • Function : Author
Sebastian Brandner
  • Function : Author
Tom Jacques
  • Function : Author
David Samuel
  • Function : Author
Alexandra Sexton Oates
  • Function : Author
Richard Saffery
  • Function : Author
Ewa Koscielniak
  • Function : Author
Suzanne Baker
  • Function : Author
Stephen Yip
  • Function : Author
Matija Snuderl
  • Function : Author
Nasir Ud Din
  • Function : Author
Kathrin Schramm
  • Function : Author
Mirjam Blattner-Johnson
  • Function : Author
Florian Selt
  • Function : Author
Jonas Ecker
  • Function : Author
Till Milde
  • Function : Author
Andreas von Deimling
  • Function : Author
Andrey Korshunov
  • Function : Author
Arie Perry
  • Function : Author
Stefan Pfister
  • Function : Author
Felix Sahm
  • Function : Author
David Solomon
  • Function : Author
David Jones

Abstract

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.

Dates and versions

hal-03982392 , version 1 (10-02-2023)

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Michaela-Kristina Keck, Martin Sill, Andrea Wittmann, Piyush Joshi, Damian Stichel, et al.. Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. Acta Neuropathologica, 2023, 145 (1), pp.49-69. ⟨10.1007/s00401-022-02516-2⟩. ⟨hal-03982392⟩
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