Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
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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.
| Original language | English |
|---|---|
| Journal | Acta Neuropathologica |
| Volume | 145 |
| Issue number | 1 |
| Pages (from-to) | 49-69 |
| Number of pages | 21 |
| ISSN | 0001-6322 |
| DOIs | |
| Publication status | Published - Jan 2023 |
Bibliographical note
Correction: https://doi.org/10.1007/s00401-022-02516-2
Funding Information:
We thank the German Cancer Research Centre (DKFZ) Genomics and Proteomics Core Facility and Laura Dörner, Katharina Müller, Lea Hofmann (Department of Neuropathology, Institute of Pathology at the University Hospital Heidelberg). This work was supported by the German Childhood Cancer Foundation (“Neuropath 2.0—Increasing diagnostic accuracy in pediatric neurooncology”; DKS 2015.01), the Everest Centre for Low-Grade Paediatric Brain Tumour Research (The Brain Tumour Charity, UK; GN-000382), the Brain Tumor Charity (UK), grant number QfC_2019/1_10507, the German Federal Ministry of Education and Research (BMBF), and Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA). A subset of the human tissue was obtained from the CRB-Cancer, CHU de Bordeaux. A subset of the human tissue was obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 19/001) which is funded by the Medical Research Council and Brain Tumour Research UK. S. Brandner was also supported by the Department of Health’s NIHR Biomedical Research Centre's funding scheme to University College London Hospitals. Ulrich Schüller was supported by the Fördergemeinschaft Kinderkrebszentrum Hamburg, Germany. Pediatric brain tumor research in the Solomon Lab is supported by the Morgan Adams Foundation, the Yuvaan Tiwari Foundation, and a Developmental Research Program award from the UCSF Brain Tumor SPORE grant from the National Cancer Institute, National Institutes of Health (P50 CA097257). DNA methylation profiling at NYU was in part supported by grants from the Friedberg Charitable Foundation, the Sohn Conference Foundation and the Making Headway Foundation (to M. Snuderl.). Pediatric brain tumor research at Karolinska Institutet as well as The Swedish Childhood Tumor Biobank (Karolinska Institutet, Stockholm, Sweden) were supported by the Swedish Childhood Cancer Fund. The molecular biology lab at the Olgahospital/Klinikum Stuttgart (Stuttgart, Germany) was supported by the Förderkreis Krebskranke Kinder e.V Stuttgart.
Funding Information:
We thank the German Cancer Research Centre (DKFZ) Genomics and Proteomics Core Facility and Laura Dörner, Katharina Müller, Lea Hofmann (Department of Neuropathology, Institute of Pathology at the University Hospital Heidelberg). This work was supported by the German Childhood Cancer Foundation (“Neuropath 2.0—Increasing diagnostic accuracy in pediatric neurooncology”; DKS 2015.01), the Everest Centre for Low-Grade Paediatric Brain Tumour Research (The Brain Tumour Charity, UK; GN-000382), the Brain Tumor Charity (UK), grant number QfC_2019/1_10507, the German Federal Ministry of Education and Research (BMBF), and Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA). A subset of the human tissue was obtained from the CRB-Cancer, CHU de Bordeaux. A subset of the human tissue was obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 19/001) which is funded by the Medical Research Council and Brain Tumour Research UK. S. Brandner was also supported by the Department of Health’s NIHR Biomedical Research Centre's funding scheme to University College London Hospitals. Ulrich Schüller was supported by the Fördergemeinschaft Kinderkrebszentrum Hamburg, Germany. Pediatric brain tumor research in the Solomon Lab is supported by the Morgan Adams Foundation, the Yuvaan Tiwari Foundation, and a Developmental Research Program award from the UCSF Brain Tumor SPORE grant from the National Cancer Institute, National Institutes of Health (P50 CA097257). DNA methylation profiling at NYU was in part supported by grants from the Friedberg Charitable Foundation, the Sohn Conference Foundation and the Making Headway Foundation (to M. Snuderl.). Pediatric brain tumor research at Karolinska Institutet as well as The Swedish Childhood Tumor Biobank (Karolinska Institutet, Stockholm, Sweden) were supported by the Swedish Childhood Cancer Fund. The molecular biology lab at the Olgahospital/Klinikum Stuttgart (Stuttgart, Germany) was supported by the Förderkreis Krebskranke Kinder e.V Stuttgart.
Publisher Copyright:
© 2022, The Author(s).
- Molecular neuro-oncology, Pediatric cancer, PLAGL1, PLAGL2
Research areas
ID: 363555537