ATRX基因突变、激酶融合和異型特征的脑神经元胶样肿瘤（GTAKA）：经常出现NTRK基因融合的一种分子学上独特的脑肿瘤类型。
Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.
发表日期：2023 Mar 18
作者：
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
来源：
ACTA NEUROPATHOLOGICA
摘要：
神经胶质细胞瘤是一组异质性的中枢神经系统肿瘤，对精确诊断可能存在挑战。分子方法在分类这些肿瘤方面非常有用——可以区分恶性组织的相似之处，以及识别之前未曾发现的肿瘤类型。我们使用无监督的DNA甲基化数据可视化方法，发现了一组新型的肿瘤（n = 20），这组肿瘤与所有已知的中枢神经系统肿瘤类型分离成一个簇。分子分析揭示，所有这些肿瘤（16/16，100%）都有ATRX改变（通过DNA测序和/或免疫组化），并且多数肿瘤有涉及受体酪氨酸激酶（RTK）的可靶向基因融合（大部分为NTRK1-3）。此外，拷贝数分析显示，55%的病例中CDKN2A/B呈纯合性缺失。组织学和免疫组化研究表明，神经胶质细胞瘤的核呈同质性、圆形、经常浓缩，周核透明，有高度有丝分裂活性和微血管增生。肿瘤主要位于幕上（84%），患者中位年龄为19岁。存活数据有限（n = 18），但表明与其他神经胶质细胞瘤相比，其生物学特征更具侵袭性（中位无进展生存时间为12.5个月）。鉴于它们的分子特征以及畸形性特征，我们提出将这些肿瘤命名为带有ATRX改变、激酶融合和畸形性特征的神经胶质细胞瘤（GTAKA）。总之，我们的研究发现了一种新型的神经胶质细胞瘤，由不同的RTK融合驱动，伴随着ATRX的反复改变和CDKN2A/B的纯合性缺失。针对NTRK的治疗方法可能代表治疗这些肿瘤患者的一个疗效明显的选择。©2023年作者。
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.© 2023. The Author(s).