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

Keck, Michaela Kristina (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Sill, Martin (author): German Cancer Research Centre,Hopp Children’s Cancer Center Heidelberg (KiTZ)

Wittmann, Andrea (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Joshi, Piyush (author): Hopp Children’s Cancer Center Heidelberg (KiTZ)

Stichel, Damian (author): German Cancer Research Centre,University Hospital Heidelberg

Beck, Pengbo (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre,Heidelberg University

Okonechnikow, Konstantin (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Sievers, Philipp (author): University Hospital Heidelberg,German Cancer Research Centre

Wefers, Annika K. (author): University Medical Center Hamburg-Eppendorf

Roncaroli, Federico (author): University of Manchester

Avula, Shivaram (author): Alder Hey Children’s NHS Foundation Trust

McCabe, Martin G. (author): University of Manchester

Hayden, James T. (author): Alder Hey Children’s NHS Foundation Trust

Wesseling, Pieter (author): Academic Medical Center of University of Amsterdam (AMC),Princess Maxima Center for Pediatric Oncology/Hematology

Øra, Ingrid (author): Lund University,Lunds universitet,Childhood Cancer Research Unit,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital

Nistér, Monica (author): Karolinska Institutet,Karolinska Institute

Kranendonk, Mariëtte E.G. (author): Princess Maxima Center for Pediatric Oncology/Hematology

Tops, Bastiaan B.J. (author): Princess Maxima Center for Pediatric Oncology/Hematology

Zapotocky, Michal (author): University Hospital Motol

Zamecnik, Josef (author): University Hospital Motol

Vasiljevic, Alexandre (author): Lyon Civil Hospital / Hospices Civils de Lyon

Fenouil, Tanguy (author): Lyon Civil Hospital / Hospices Civils de Lyon

Meyronet, David (author): Lyon Civil Hospital / Hospices Civils de Lyon

von Hoff, Katja (author): Berlin Institute of Health (BIH)

Schüller, Ulrich (author): Research Institute Children’s Cancer Center Hamburg,University Medical Center Hamburg-Eppendorf

Loiseau, Hugues (author): University of Bordeaux

Figarella-Branger, Dominique (author): Aix-Marseille University

Kramm, Christof M. (author): University Medical Center Göttingen

Sturm, Dominik (author): University Hospital Heidelberg,Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Scheie, David (author): Copenhagen University Hospital

Rauramaa, Tuomas (author): Kuopio University Hospital

Pesola, Jouni (author): Kuopio University Hospital

Gojo, Johannes (author): Medical University of Vienna

Haberler, Christine (author): Medical University of Vienna

Brandner, Sebastian (author): National Hospital for Neurology and Neurosurgery,University College London

Jacques, Tom (author): UCL Institute of Child Health

Sexton Oates, Alexandra (author): University of Melbourne

Saffery, Richard (author): University of Melbourne

Koscielniak, Ewa (author): Klinikum Stuttgart Olgahospital

Baker, Suzanne J. (author): St Jude Children´s Research Hospital, Memphis

Yip, Stephen (author): University of British Columbia

Snuderl, Matija (author): NYU Grossman School of Medicine

Ud Din, Nasir (author): Aga Khan University, Pakistan

Samuel, David (author): Valley Children’s Hospital

Schramm, Kathrin (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Blattner-Johnson, Mirjam (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Selt, Florian (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre,University Hospital Heidelberg

Ecker, Jonas (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre,University Hospital Heidelberg

Milde, Till (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre,University Hospital Heidelberg

von Deimling, Andreas (author): German Cancer Research Centre,University Hospital Heidelberg

Korshunov, Andrey (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),University Hospital Heidelberg,German Cancer Research Centre

Perry, Arie (author): University of California, San Francisco

Pfister, Stefan M (author): University Hospital Heidelberg,Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

Sahm, Felix (author): German Cancer Research Centre,Hopp Children’s Cancer Center Heidelberg (KiTZ),University Hospital Heidelberg

Solomon, David A. (author): University of California, San Francisco

Jones, David T W (author): Hopp Children’s Cancer Center Heidelberg (KiTZ),German Cancer Research Centre

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2022-11-27
2023
English 21 s.
In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 145:1, s. 49-69

Related links:: http://dx.doi.org/10... (free); show more...; https://lup.lub.lu.s...; https://doi.org/10.1...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Pediatrik (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Pediatrics (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

Molecular neuro-oncology
Pediatric cancer
PLAGL1
PLAGL2

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art (subject category)
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By the author/editor: Keck, Michaela K ...; Sill, Martin; Wittmann, Andrea; Joshi, Piyush; Stichel, Damian; Beck, Pengbo; show more...; Okonechnikow, Ko ...; Sievers, Philipp; Wefers, Annika K ...; Roncaroli, Feder ...; Avula, Shivaram; McCabe, Martin G ...; Hayden, James T.; Wesseling, Piete ...; Øra, Ingrid; Nistér, Monica; Kranendonk, Mari ...; Tops, Bastiaan B ...; Zapotocky, Micha ...; Zamecnik, Josef; Vasiljevic, Alex ...; Fenouil, Tanguy; Meyronet, David; von Hoff, Katja; Schüller, Ulrich; Loiseau, Hugues; Figarella-Brange ...; Kramm, Christof ...; Sturm, Dominik; Scheie, David; Rauramaa, Tuomas; Pesola, Jouni; Gojo, Johannes; Haberler, Christ ...; Brandner, Sebast ...; Jacques, Tom; Sexton Oates, Al ...; Saffery, Richard; Koscielniak, Ewa; Baker, Suzanne J ...; Yip, Stephen; Snuderl, Matija; Ud Din, Nasir; Samuel, David; Schramm, Kathrin; Blattner-Johnson ...; Selt, Florian; Ecker, Jonas; Milde, Till; von Deimling, An ...; Korshunov, Andre ...; Perry, Arie; Pfister, Stefan ...; Sahm, Felix; Solomon, David A ...; Jones, David T W; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Pediatrics

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

Articles in the publication: Acta Neuropathol ...

By the university: Lund University; Karolinska Institutet

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