open access publication

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, 0001-6322, Volume 145, 5, Pages 667-680, 10.1007/s00401-023-02558-0

Contributors

Bogumil, Henri [1] [2] [3] Sill, Martin 0000-0001-7616-7665 [1] [2] [4] Schrimpf, Daniel 0000-0003-3063-2423 [1] [2] [3] Ismer, Britta [1] [2] [3] [4] Blume, Christina [1] [2] [3] Rahmanzade, Ramin [1] [2] [3] Hinz, Felix [1] [2] [3] Cherkezov, Asan [1] [2] [3] Banan, Rouzbeh 0000-0002-9999-576X [1] [2] [3] Friedel, Dennis [1] [2] [3] Reuss, David [1] [2] [3] Selt, Florian [1] [2] [3] [4] Ecker, Jonas [1] [2] [3] [4] Milde, Till 0000-0002-7267-1052 [1] [2] [3] [4] Pajtler, Kristian 0000-0002-3562-6121 [1] [2] [3] [4] Schittenhelm, J. [1] [2] [5] [6] Hench, Jurgen [7] Frank, Stephan [7] Boldt, Henning B. [8] [9] Kristensen, Bjarne 0000-0002-6352-0826 [8] [9] [10] [11] Scheie, David 0000-0002-8692-1198 [10] [11] Melchior, L. C. 0000-0001-7061-8859 [10] [11] Olesen, Viola [10] [11] Sehested, A. M. [11] Boue, Daniel R. [12] [13] [14] Abdullaev, Zied [15] [16] Satgunaseelan, Laveniya 0000-0002-7435-0834 [17] Kurth, Ina 0000-0001-9261-5165 [1] [2] Seidlitz, A. [1] [2] [3] [18] [19] [20] White, Christine L. [21] [22] [23] Ng, Ho-Keung 0000-0002-8807-2927 [24] [25] Chen, X. 0000-0003-3599-4909 [25] [26] Haberler, Christine [27] Deckert, M. [28] Timmer, Marco [28] Goldbrunner, Roland [28] Tauziede-Espariat, Arnault [29] [30] [31] Varlet, Pascale [29] [30] [31] Brandner, Sebastian 0000-0002-8635-7195 [32] [33] [34] [35] Alexandrescu, Sanda [36] [37] Snuderl, Matija 0000-0003-0752-0917 [38] Aldape, Kenneth 0000-0001-5119-7550 [15] [16] Korshunov, Andrey 0000-0002-5257-3623 [1] [2] [3] [4] Witt, Olaf [1] [2] [3] [4] Herold-Mende, Christel 0000-0002-1915-745X [3] Unterberg, Andreas 0000-0003-3742-3288 [3] Wick, Wolfgang 0000-0002-6171-634X [1] [2] [3] Pfister, Stefan M 0000-0002-5447-5322 [1] [2] [3] [4] von Deimling, Andreas [1] [2] [3] Jones, David T. W. 0000-0002-2036-5141 [1] [2] [4] Sahm, Felix 0000-0001-5441-1962 [1] [2] [3] [4] Sievers, Philipp 0000-0003-3237-6021 (Corresponding author) [1] [2] [3]

Affiliations

  1. [1] German Canc Consortium DKTK, DKFZ Partner Site Tubingen, Tubingen, Germany
    2. [NORA names: Germany; Europe, EU; OECD];
  2. [2] German Canc Consortium DKTK, DKFZ Partner Site Tubingen, Tubingen, Germany
    3. [NORA names: Germany; Europe, EU; OECD];
  3. [3] Heidelberg Univ Hosp, Dept Neurol & Neurooncol Program, Natl Ctr Tumor Dis NCT, Heidelberg, Germany
    4. [NORA names: Germany; Europe, EU; OECD];
  4. [4] Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany
    5. [NORA names: Germany; Europe, EU; OECD];
  5. [5] Eberhard Karls Univ Tubingen, Univ Tubingen Hosp, Ctr Neurooncol, Comprehens Canc Ctr Tubingen Stuttgart, Tubingen, Germany
    6. [NORA names: Germany; Europe, EU; OECD];

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, DNA methylation, Gene fusion, Glioneuronal tumor, NTRK

Data Provider: Clarivate

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