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, 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. [1] German Cancer Research Center
    2. [NORA names: Germany; Europe, EU; OECD];
  2. [2] University Hospital Heidelberg
    3. [NORA names: Germany; Europe, EU; OECD];
  3. [3] Hopp Children's Cancer Center Heidelberg
    4. [NORA names: Germany; Europe, EU; OECD];
  4. [4] Heidelberg University
    5. [NORA names: Germany; Europe, EU; OECD];
  5. [5] National Center for Tumor Diseases
    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, 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

  • National Cancer Institute
  • Brain Tumour Charity
  • Cancer Australia
  • National Institute of Dental and Craniofacial Research
  • Else Kröner-Fresenius-Stiftung
  • Hertie Foundation
  • German Cancer Research Center
  • Brain Tumour Research

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