TY - JOUR

T1 - Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA)

T2 - a molecularly distinct brain tumor type with recurrent NTRK gene fusions

AU - Bogumil, Henri

AU - Sill, Martin

AU - Schrimpf, Daniel

AU - Ismer, Britta

AU - Blume, Christina

AU - Rahmanzade, Ramin

AU - Hinz, Felix

AU - Cherkezov, Asan

AU - Banan, Rouzbeh

AU - Friedel, Dennis

AU - Reuss, David E.

AU - Selt, Florian

AU - Ecker, Jonas

AU - Milde, Till

AU - Pajtler, Kristian W.

AU - Schittenhelm, Jens

AU - Hench, Jürgen

AU - Frank, Stephan

AU - Boldt, Henning B.

AU - Kristensen, Bjarne Winther

AU - Scheie, David

AU - Melchior, Linea C.

AU - Olesen, Viola

AU - Sehested, Astrid

AU - Boué, Daniel R.

AU - Abdullaev, Zied

AU - Satgunaseelan, Laveniya

AU - Kurth, Ina

AU - Seidlitz, Annekatrin

AU - White, Christine L.

AU - Ng, Ho Keung

AU - Shi, Zhi Feng

AU - Haberler, Christine

AU - Deckert, Martina

AU - Timmer, Marco

AU - Goldbrunner, Roland

AU - Tauziède-Espariat, Arnault

AU - Varlet, Pascale

AU - Brandner, Sebastian

AU - Alexandrescu, Sanda

AU - Snuderl, Matija

AU - Aldape, Kenneth

AU - Korshunov, Andrey

AU - Witt, Olaf

AU - Herold-Mende, Christel

AU - Unterberg, Andreas

AU - Wick, Wolfgang

AU - Pfister, Stefan M.

AU - von Deimling, Andreas

AU - Jones, David T.W.

AU - Sahm, Felix

AU - Sievers, Philipp

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - ATRX

KW - DNA methylation

KW - Gene fusion

KW - Glioneuronal tumor

KW - NTRK

U2 - 10.1007/s00401-023-02558-0

DO - 10.1007/s00401-023-02558-0

M3 - Journal article

C2 - 36933012

AN - SCOPUS:85150217489

VL - 145

SP - 667

EP - 680

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -