Article, 2023
Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions
Acta Neuropathologica,
ISSN
0001-6322,
1432-0533,
Volume 145,
5,
Pages 667-680,
10.1007/s00401-023-02558-0
Contributors
Bogumil, Henri
[1]
[2]
Sill, Martin
0000-0001-7616-7665
[1]
[3]
Schrimpf, Daniel
0000-0003-3063-2423
[1]
[2]
Ismer, Britta
[1]
[3]
[4]
Blume, Christina
[1]
[2]
Rahmanzade, Ramin
[1]
[2]
Hinz, Felix
[1]
[2]
Cherkezov, Asan
[1]
[2]
Banan, Rouzbeh
0000-0002-9999-576X
[1]
[2]
Friedel, Dennis
[1]
[2]
Reuss, David E
[1]
[2]
Selt, Florian
[1]
[2]
[3]
[5]
Ecker, Jonas
[1]
[2]
[3]
[5]
Milde, Till
[1]
[2]
[3]
[5]
Pajtler, Kristian W
0000-0002-3562-6121
[1]
[2]
[3]
Schittenhelm, Jens
[1]
[6]
[7]
Hench, Jürgen
0000-0002-9884-1240
[8]
Frank, Stephan
[8]
Boldt, Henning Bünsow
[9]
[10]
Kristensen, Bjarne Winther
0000-0002-6352-0826
[9]
[10]
[11]
[12]
Scheie, David
0000-0002-8692-1198
[12]
Melchior, Linea Cecilie
0000-0001-7061-8859
[12]
Olesen, Viola
[12]
Sehested, Astrid Marie
[13]
Boué, Daniel R
[14]
Abdullaev, Zied
[15]
Satgunaseelan, Laveniya Satgunaseelan
0000-0002-7435-0834
[16]
Kurth, Ina
0000-0001-9261-5165
[1]
Seidlitz, Annekatrin
[1]
[5]
[17]
[18]
White, Christine L
0000-0002-5920-0029
[19]
[20]
[21]
Ng, Ho-Keung
0000-0002-2614-2213
[22]
[23]
Shi, Zhi-Feng
[23]
[24]
[25]
Haberler, Christine C
[26]
Deckert, Martina
[27]
Timmer, Marco
[27]
Goldbrunner, Roland
[27]
Tauziède-Espariat, Arnault
[28]
[29]
Varlet, Pascale
0000-0002-8164-1517
[28]
[29]
Brandner, Sebastian G P
0000-0002-9821-0342
[30]
Alexandrescu, Sanda
[31]
Snuderl, Matija
0000-0003-0752-0917
[32]
Aldape, Kenneth D
0000-0001-5119-7550
[15]
Korshunov, Andrey
0000-0002-5257-3623
[1]
[2]
[3]
Witt, Olaf
[1]
[2]
[3]
[5]
Herold-Mende, Christel C
0000-0002-1915-745X
[2]
Unterberg, Andreas
[2]
Wick, Wolfgang
0000-0002-6171-634X
[1]
[2]
Pfister, Stefan Michael
0000-0002-5447-5322
[1]
[2]
[3]
[5]
Von Deimling, Andreas
0000-0002-5863-540X
[1]
[2]
Jones, David T W
0000-0002-2036-5141
[1]
[3]
Sahm, Felix
[1]
[2]
[3]
[5]
Sievers, Philipp
0000-0003-3237-6021
(Corresponding author)
[1]
[2]
Affiliations
- [1]
German Cancer Research Center
[NORA names:
Germany; Europe, EU; OECD];
- [2]
University Hospital Heidelberg
[NORA names:
Germany; Europe, EU; OECD];
- [3]
Hopp Children's Cancer Center Heidelberg
[NORA names:
Germany; Europe, EU; OECD];
- [4]
Heidelberg University
[NORA names:
Germany; Europe, EU; OECD];
- [5]
National Center for Tumor Diseases
[NORA names:
Germany; Europe, EU; OECD];
(... more)
- [6]
University of Tübingen
[NORA names:
Germany; Europe, EU; OECD];
- [7]
Universitätsklinikum Tübingen
[NORA names:
Germany; Europe, EU; OECD];
- [8]
University Hospital of Basel
[NORA names:
Switzerland; Europe, Non-EU; OECD];
- [9]
Odense University Hospital
[NORA names:
Region of Southern Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [10]
University of Southern Denmark
[NORA names:
SDU University of Southern Denmark;
University; Denmark; Europe, EU; Nordic; OECD];
- [11]
University of Copenhagen
[NORA names:
KU University of Copenhagen;
University; Denmark; Europe, EU; Nordic; OECD];
- [12]
Rigshospitalet
[NORA names:
Capital Region of Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [13]
Copenhagen University Hospital
[NORA names:
Capital Region of Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [14]
The Ohio State University
[NORA names:
United States; America, North; OECD];
- [15]
Center for Cancer Research
[NORA names:
United States; America, North; OECD];
- [16]
Royal Prince Alfred Hospital
[NORA names:
Australia; Oceania; OECD];
- [17]
Helmholtz-Zentrum Dresden-Rossendorf
[NORA names:
Germany; Europe, EU; OECD];
- [18]
TU Dresden
[NORA names:
Germany; Europe, EU; OECD];
- [19]
Hudson Institute of Medical Research
[NORA names:
Australia; Oceania; OECD];
- [20]
Monash University
[NORA names:
Australia; Oceania; OECD];
- [21]
Victorian Clinical Genetics Services
[NORA names:
Australia; Oceania; OECD];
- [22]
Chinese University of Hong Kong
[NORA names:
China; Asia, East];
- [23]
Hong Kong and Shanghai Brain Consortium (HSBC), Hong Kong, China
[NORA names:
China; Asia, East];
- [24]
Fudan University
[NORA names:
China; Asia, East];
- [25]
Huashan Hospital
[NORA names:
China; Asia, East];
- [26]
Medical University of Vienna
[NORA names:
Austria; Europe, EU; OECD];
- [27]
University of Cologne
[NORA names:
Germany; Europe, EU; OECD];
- [28]
Centre Hospitalier Sainte-Anne
[NORA names:
France; Europe, EU; OECD];
- [29]
Institute of Psychiatry and Neuroscience of Paris
[NORA names:
France; Europe, EU; OECD];
- [30]
National Hospital for Neurology and Neurosurgery
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [31]
Boston Children's Hospital
[NORA names:
United States; America, North; OECD];
- [32]
New York University Langone Medical Center
[NORA names:
United States; America, North; OECD]
(less)
Abstract
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors—distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.
Keywords
ATRX,
ATRX alterations,
CDKN2A/B,
CDKN2A/B.,
CNS,
CNS neoplasms,
DNA methylation data,
Molecular,
NTRK,
NTRK gene fusions,
RTK,
activity,
age,
aggressive biology,
alterations,
analysis,
anaplastic features,
approach,
biology,
brain tumor types,
cases,
characteristics,
clearing,
clusters,
condensation nuclei,
copy,
copy number profiles,
data,
deletion of CDKN2A/B,
features,
findings,
fusion,
gene fusions,
glioneuronal tumor,
group,
group of tumors,
heterogeneous group,
histologic mimics,
homozygous deletion,
homozygous deletion of CDKN2A/B,
immunohistochemical investigation,
inhibition,
investigation,
kinase,
kinase fusions,
method,
methylation data,
microvascular proliferation,
mimics,
mitotic activity,
molecular analysis,
molecular characteristics,
molecular methods,
neoplasms,
nucleus,
options,
patients,
perinuclear clearing,
profile,
proliferation,
receptor tyrosine-kinase,
receptors,
recurrent alterations,
survival,
survival data,
targetable gene fusions,
targeted approach,
therapeutic options,
tumor,
tumor types,
type,
tyrosine-kinase,
unrecognized type,
years
Funders
Data Provider: Digital Science