Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.

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.

• Authors: Henri Bogumil, Martin Sill, Daniel Schrimpf, Britta Ismer, Christina Blume, Ramin Rahmanzade, Felix Hinz, Asan Cherkezov, Rouzbeh Banan, Dennis Friedel, David E Reuss, Florian Selt, Jonas Ecker, Till Milde, Kristian W Pajtler, Jens Schittenhelm, Jürgen Hench, Stephan Frank, Henning B Boldt, Bjarne Winther Kristensen, David Scheie, Linea C Melchior, Viola Olesen, Astrid Sehested, Daniel R Boué, Zied Abdullaev, Laveniya Satgunaseelan, Ina Kurth, Annekatrin Seidlitz, Christine L White, Ho-Keung Ng, Zhi-Feng Shi, Christine Haberler, Martina Deckert, Marco Timmer, Roland Goldbrunner, Arnault Tauziède-Espariat, Pascale Varlet, Sebastian Brandner, Sanda Alexandrescu, Matija Snuderl, Kenneth Aldape, Andrey Korshunov, Olaf Witt, Christel Herold-Mende, Andreas Unterberg, Wolfgang Wick, Stefan M Pfister, Andreas von Deimling, David T W Jones, Felix Sahm, Philipp Sievers
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 145 Issue 5 Pg. 667-680 (05 2023) ISSN: 1432-0533 [Electronic] Germany
• PMID: 36933012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• ATRX protein, human
• Biomarkers, Tumor
• Receptor Protein-Tyrosine Kinases
• X-linked Nuclear Protein

Topics

• Humans
• Young Adult
• Biomarkers, Tumor (genetics)
• Brain (pathology)
• Brain Neoplasms (genetics, pathology)
• Central Nervous System Neoplasms
• Gene Fusion
• Neoplasms, Neuroepithelial (genetics, pathology)
• Receptor Protein-Tyrosine Kinases (genetics)
• X-linked Nuclear Protein (genetics)