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PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration

Keck, M. K.
; 
Al-Hussaini, M.
; 
Amayiri, N.
; 
Yiadom, A. A. B.
; 
Chamyan, G.
; 
Cheesman, E.
; 
Faure-Conter, C.
; 
Garcia-Ariza, M.
; 
Gauchotte, G.
; 
Hasselblatt, M.
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Abstract
CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5' fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.
Authors
Keck, M. K.
Al-Hussaini, M.
Amayiri, N.
Yiadom, A. A. B.
Chamyan, G.
Cheesman, E.
Faure-Conter, C.
Garcia-Ariza, M.
Gauchotte, G.
Hasselblatt, M.
Jorgensen, M.
Kilday, J. P.
Lamas, G.
Lavarino, C.
Li, M. M.
Lubieniecki, F.
Maher, O. M.
Meyronet, D.
Mueller, J.
Santi, M.
Schüller, U.
Seidinger, A. L.
Sill, M.
Sudhakar, S.
García, M. T.
Tauziede-Espariat, A.
Varlet, P.
Vasiljevic, A.
Wittmann, A.
von Deimling, A.
Solomon, D. A.
Sahm, F.
Tietze, A.
von Hoff, K.
Sievers, P.
Jones, D. T. W.
Affiliation
Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman, Jordan. Department of Pediatric Oncology, Neuro-Oncology Service, King Hussein Cancer Center, Amman, Jordan. Department of Pediatric Hematology and Oncology, Nicklaus Children's Hospital, Miami, FL, USA. Department of Paediatric Histopathology, Royal Manchester Children's Hospital, Manchester, UK. Institut d'Hemato-oncologie Pediatrique, Lyon, France. Pediatric Hematology and Oncology Unit, Department of Pediatrics, Biobizkaia Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain. Department of Biopathology, CHRU-ICL, Tumorothèque BB-0033-00035, INSERM U1256 NGERE, Vandoeuvre-lès-Nancy, France. Institute of Neuropathology, University Hospital Münster, Münster, Germany. Oncology Department Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK. The Centre for Paediatric, Teenage and Young Adult Cancer, Division of Cancer Sciences, The University of Manchester, Manchester, UK. Children's Brain Tumour Research Network (CBTRN), Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, UK. Department of Pathology, Hospital Nacional de Pediatria Dr JP Garrahan, Buenos Aires, Argentina. Laboratory of Molecular Oncology, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, 08950, Barcelona, Spain. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. Institut de Pathologie Multisite-Site Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. Boldrini Children's Center, Laboratory of Molecular Biology, Campinas, Brazil. Department of Neuroradiology, Great Ormond Street Hospital for Children, London, UK. Department of Paediatric Hematology and Oncology, Álvaro Cunqueiro Hospital, Galicia Sur Research Foundation, Vigo, Spain. Department of Neuropathology, GHU Paris - Psychiatry and Neuroscience, Sainte-Anne Hospital, Paris, France. Université de Paris, UMR S1266, INSERM, IMA-BRAIN, Institute of Psychiatry and Neurosciences of Paris, Paris, France. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. Institute of Neuroradiology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Department of Paediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. philipp.sievers@med.uni-heidelberg.de. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. philipp.sievers@med.uni-heidelberg.de. Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. david.jones@kitz-heidelberg.de. National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. david.jones@kitz-heidelberg.de. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. david.jones@kitz-heidelberg.de.
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2025
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All Paterson Institute for Cancer Research
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Keck MK, Al-Hussaini M, Amayiri N, Yiadom AAB, Chamyan G, Cheesman E, et al. PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration. Acta Neuropathol. 2025 Aug 2;150(1):12. PubMed PMID: 40751809. Pubmed Central PMCID: PMC12317869. Epub 2025/08/03. eng.
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https://christie.openrepository.com/handle/10541/627989
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