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Molecular methods are highly useful in classifying these tumors\u2014distinguishing 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 (<jats:italic>n<\/jats:italic>\u2009=\u200920) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed <jats:italic>ATRX<\/jats:italic> alterations (in 16\/16 cases by DNA sequencing and\/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK;\u00a0mostly <jats:italic>NTRK1-3<\/jats:italic>) in all of these tumors (16\/16; 100%). In addition, copy number profiling showed homozygous deletions of <jats:italic>CDKN2A\/B<\/jats:italic> 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\u00a0years. Survival data were limited (<jats:italic>n<\/jats:italic>\u2009=\u200918) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5\u00a0months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with <jats:italic>ATRX<\/jats:italic> 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 <jats:italic>ATRX<\/jats:italic> and homozygous deletions of <jats:italic>CDKN2A\/B<\/jats:italic>. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.<\/jats:p>","DOI":"10.1007\/s00401-023-02558-0","type":"journal-article","created":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T08:02:41Z","timestamp":1679126561000},"page":"667-680","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene 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