Article, 2022
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,
ISSN
0001-6322,
1432-0533,
Volume 145,
1,
Pages 49-69,
10.1007/s00401-022-02516-2
Contributors
Keck, Michaela-Kristina
[1]
[2]
Sill, Martin
0000-0001-7616-7665
[1]
[2]
Wittmann, Andrea
[1]
[2]
Joshi, Piyush K
0000-0002-5631-336X
[1]
Stichel, Damian
[2]
[3]
Beck, Pengbo
[1]
[2]
[4]
Okonechnikow, Konstantin
[1]
[2]
Sievers, Philipp
0000-0003-3237-6021
[2]
[3]
Wefers, Annika K
0000-0001-9394-8519
[5]
Roncaroli, Federico
0000-0003-3650-5572
[6]
Avula, Shivaram
0000-0003-1742-7206
[7]
Mccabe, Martin G
[6]
Hayden, James T
[7]
Wesseling, Pieter
0000-0001-5453-5201
[8]
[9]
Øra, Ingrid
0000-0002-3931-4125
[10]
[11]
Nistér, Monica
[12]
Kranendonk, Mariëtte E G
0000-0001-9683-7494
[9]
Tops, Bastiaan B J
0000-0002-1699-8210
[9]
Zapotocky, Michal
0000-0002-9013-2546
[13]
Zamecnik, Josef
[13]
Vasiljevic, Alexandre
[14]
Fenouil, Tanguy
0000-0002-2747-763X
[14]
Meyronet, David
[14]
Von Hoff, Katja
0000-0002-5669-8546
[15]
Schüller, Ulrich
0000-0002-8731-1121
[5]
[16]
Loiseau, Hugues
[17]
Figarella-Branger, Dominique F
0000-0002-3604-887X
[18]
Kramm, Christof Maria
0000-0002-5017-926X
[19]
Sturm, Dominik
0000-0003-0250-1696
[1]
[2]
[3]
Scheie, David
0000-0002-8692-1198
[20]
Rauramaa, Tuomas H
0000-0002-2250-327X
[21]
Pesola, Jouni
[21]
Gojo, Johannes Salomon
0000-0002-8113-3416
[22]
Haberler, Christine C
[22]
Brandner, Sebastian G P
0000-0002-9821-0342
[23]
Jacques, Tom
[24]
Sexton-Oates, Alexandra
[25]
[26]
Saffery, Richard R S
0000-0002-9510-4181
[25]
[26]
Koscielniak, Ewa
[27]
Baker, Suzanne J
0000-0002-5833-472X
[28]
Yip, Stephen
[29]
Snuderl, Matija
0000-0003-0752-0917
[30]
Ud Din, Nasir
[31]
Samuel, David
[32]
Schramm, Kathrin
[1]
[2]
Blattner-Johnson, Mirjam
[1]
[2]
Selt, Florian
[1]
[2]
[3]
Ecker, Jonas
[1]
[2]
[3]
Milde, Till
0000-0002-7267-1052
[1]
[2]
[3]
Von Deimling, Andreas
0000-0002-5863-540X
[2]
[3]
Korshunov, Andrey
0000-0002-5257-3623
[1]
[2]
[3]
Perry, Arie
0000-0002-8300-7261
[33]
Pfister, Stefan Michael
0000-0002-5447-5322
[1]
[2]
[3]
Sahm, Felix
0000-0001-5441-1962
[1]
[2]
[3]
Solomon, David A
(Corresponding author)
[33]
Jones, David T W
0000-0002-2036-5141
(Corresponding author)
[1]
[2]
Affiliations
- [1]
Hopp Children's Cancer Center Heidelberg
[NORA names:
Germany; Europe, EU; OECD];
- [2]
German Cancer Research Center
[NORA names:
Germany; Europe, EU; OECD];
- [3]
University Hospital Heidelberg
[NORA names:
Germany; Europe, EU; OECD];
- [4]
Heidelberg University
[NORA names:
Germany; Europe, EU; OECD];
- [5]
University Medical Center Hamburg-Eppendorf
[NORA names:
Germany; Europe, EU; OECD];
(... more)
- [6]
University of Manchester
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [7]
Alder Hey Children's NHS Foundation Trust
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [8]
Amsterdam University Medical Centers
[NORA names:
Netherlands; Europe, EU; OECD];
- [9]
Princess Máxima Center
[NORA names:
Netherlands; Europe, EU; OECD];
- [10]
Lund University
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [11]
Skåne University Hospital
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [12]
Karolinska Institutet
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [13]
University Hospital in Motol
[NORA names:
Czechia; Europe, EU; OECD];
- [14]
Hospices Civils de Lyon
[NORA names:
France; Europe, EU; OECD];
- [15]
Humboldt-Universität zu Berlin
[NORA names:
Germany; Europe, EU; OECD];
- [16]
Kinderkrebs-Zentrum Hamburg
[NORA names:
Germany; Europe, EU; OECD];
- [17]
University of Bordeaux
[NORA names:
France; Europe, EU; OECD];
- [18]
Hôpital de la Timone
[NORA names:
France; Europe, EU; OECD];
- [19]
Universitätsmedizin Göttingen
[NORA names:
Germany; Europe, EU; OECD];
- [20]
Rigshospitalet
[NORA names:
Capital Region of Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [21]
University of Eastern Finland
[NORA names:
Finland; Europe, EU; Nordic; OECD];
- [22]
Medical University of Vienna
[NORA names:
Austria; Europe, EU; OECD];
- [23]
National Hospital for Neurology and Neurosurgery
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [24]
University College London
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [25]
Royal Children's Hospital
[NORA names:
Australia; Oceania; OECD];
- [26]
University of Melbourne
[NORA names:
Australia; Oceania; OECD];
- [27]
Olgahospital
[NORA names:
Germany; Europe, EU; OECD];
- [28]
St. Jude Children's Research Hospital
[NORA names:
United States; America, North; OECD];
- [29]
University of British Columbia
[NORA names:
Canada; America, North; OECD];
- [30]
New York University Langone Medical Center
[NORA names:
United States; America, North; OECD];
- [31]
Aga Khan University
[NORA names:
Pakistan; Asia, South];
- [32]
Children's Hospital Central California
[NORA names:
United States; America, North; OECD];
- [33]
University of California, San Francisco
[NORA names:
United States; America, North; OECD]
(less)
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.
Keywords
CNS embryonal tumors,
CNS tumor classification,
CNS tumors,
CYP2W1,
ChIP-seq,
ChIP-seq analysis,
DNA,
PLAGL1,
PLAGL2,
RET,
RNA-seq,
Wnt/b-catenin,
Wnt/b-catenin pathway,
absence,
accurate diagnosis,
adolescents,
adult counterparts,
aged 0,
alterations,
amplification,
analysis,
associated with intermediate survival,
biology,
brainstem,
cancer-related deaths,
cause,
cause of cancer-related death,
cell of origin,
cells,
central nervous system,
central nervous system embryonal tumors,
central nervous system tumor types,
cerebellum,
cerebral hemispheres,
characteristics,
childhood,
children,
children aged 0,
classification,
combination,
components,
control,
copy,
copy number,
counterparts,
data,
death,
diagnosis,
differentiation,
dysregulation,
early childhood,
embryonal tumors,
expression of markers,
expression signatures,
factors,
female patients,
focal high-level amplification,
gene expression signatures,
genes,
genetic alterations,
hemisphere,
heterogeneity,
high-level amplification,
histology,
histopathological spectrum,
impair accurate diagnosis,
imprinted genes,
infants,
intermediate survival,
male,
male patients,
markers,
molecular heterogeneity,
nervous system,
neuroaxis,
neuronal differentiation,
number,
optimal treatment strategy,
origin,
overall survival,
overexpression,
pathway,
patient characteristics,
patients,
pediatric central nervous system,
recurrent genetic alterations,
regulatory subsets,
robust expression,
signature,
spectra,
strategies,
survival,
survival data,
system,
toddlers,
transcription,
transcription factors,
treatment strategies,
tumor,
tumor classification,
tumor types,
type,
years
Funders
Data Provider: Digital Science