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.

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

“…Among the detected NTRK2 -fusions, the most likely to carry biological relevance is LRRFIP2::NTRK2 involving the 3’ end of NTRK2 with the protein kinase domain. It is worth noting, that the co-occurance of NTRK2 -rearrangement and ATRX loss raises the possibility that this tumor represents the novel GTAKA category 8 . Loss-of-function mutation of MLH1 , accompanied MLH1 and PMS2 loss as well as high TMB are likely to be related to therapy-induced hypermutation in this case, since both MLH1 and PMS2 expressions were intact in the primary tumor sample 38 .…”

“…ATRX-deficient IDH-wildtype and H3-wildtype adult gliomas are rare and include mostly GBs and some recently described new entities, such as high-grade astrocytoma with piloid features (HGAP) 7 and glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) 8 . Many cases of these latter entities previously fell into the GB category.…”

Identification of a novel SH3PXD2B::FER fusion in a case of plexiform myofibroblastic tumor and review of the literature

“…An MYO5A::FER fusion has been described in a case of glioneuronal tumor belonging to an emerging molecular group of brain tumors known as GTAKA (Glioneuronal tumor with ATRX alteration, kinase fusion, and anaplastic features). This type of tumor is characterized by potentially targetable gene fusions involving receptor tyrosine‐kinases and recurrent alterations in ATRX and homozygous deletions of CDKN2A/B 24 …”

Atrx loss as a promising screening tool for the identification of diffuse midline glioma subtype, H3K27/MAPKinase co-altered

“…In this context, a loss of ATRX expression, in conjunction with p53, seems to be good indicator of this novel DMG subtype. This hallmark adds a novel differential diagnostic tool that can be used to distinguish these tumors from other gliomas harboring this loss of expression (astrocytomas, IDH- mutant, high-grade astrocytomas with piloid features, diffuse hemispheric gliomas, H3 G34-mutant, and the novel glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features) [ 1 , 7 , 14 ]. These data reinforce the idea that an official diagnosis must integrate all clinical (age of onset), radiological (midline location or hemispheric), histopathological (growth pattern and differentiation), and molecular results.…”