PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration.
Por:
Keck MK, Al-Hussaini M, Amayiri N, Yiadom AAB, Chamyan G, Cheesman E, Faure-Conter C, Garcia-Ariza M, Gauchotte G, Hasselblatt M, Jorgensen M, Kilday JP, Lamas G, Lavarino C, Li MM, Lubieniecki F, Maher OM, Meyronet D, Mueller J, Santi M, Schüller U, Seidinger AL, Sill M, Sudhakar S, García MT, Tauziede-Espariat A, Varlet P, Vasiljevic A, Wittmann A, von Deimling A, Solomon DA, Sahm F, Tietze A, von Hoff K, Sievers P and Jones DTW
Publicada:
2 ago 2025
Ahead of Print:
2 ago 2025
Resumen:
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.
Filiaciones:
Keck MK:
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
Al-Hussaini M:
Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman, Jordan
Amayiri N:
Department of Pediatric Oncology, Neuro-Oncology Service, King Hussein Cancer Center, Amman, Jordan
Yiadom AAB:
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
Chamyan G:
Department of Pediatric Hematology and Oncology, Nicklaus Children's Hospital, Miami, FL, USA
Cheesman E:
Department of Paediatric Histopathology, Royal Manchester Children's Hospital, Manchester, UK
Faure-Conter C:
Institut d'Hemato-oncologie Pediatrique, Lyon, France
Garcia-Ariza M:
Pediatric Hematology and Oncology Unit, Department of Pediatrics, Biobizkaia Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain
Gauchotte G:
Department of Biopathology, CHRU-ICL, Tumorothèque BB-0033-00035, INSERM U1256 NGERE, Vandoeuvre-lès-Nancy, France
Hasselblatt M:
Institute of Neuropathology, University Hospital Münster, Münster, Germany
Jorgensen M:
Oncology Department Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
Kilday JP:
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
Lamas G:
Department of Pathology, Hospital Nacional de Pediatria Dr JP Garrahan, Buenos Aires, Argentina
Lavarino C:
Laboratory of Molecular Oncology, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, 08950, Barcelona, Spain
Li MM:
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
Lubieniecki F:
Department of Pathology, Hospital Nacional de Pediatria Dr JP Garrahan, Buenos Aires, Argentina
Maher OM:
Department of Pediatric Hematology and Oncology, Nicklaus Children's Hospital, Miami, FL, USA
Meyronet D:
Institut de Pathologie Multisite-Site Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
Mueller J:
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
Santi M:
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
Schüller U:
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
Seidinger AL:
Boldrini Children's Center, Laboratory of Molecular Biology, Campinas, Brazil
Sill M:
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
Sudhakar S:
Department of Neuroradiology, Great Ormond Street Hospital for Children, London, UK
García MT:
Department of Paediatric Hematology and Oncology, Álvaro Cunqueiro Hospital, Galicia Sur Research Foundation, Vigo, Spain
Tauziede-Espariat A:
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
Varlet P:
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
Vasiljevic A:
Institut de Pathologie Multisite-Site Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
Wittmann A:
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
von Deimling A:
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
Solomon DA:
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA
Sahm F:
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 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
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Tietze A:
Institute of Neuroradiology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
von Hoff K:
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
Sievers P:
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
Jones DTW:
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
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