Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Arnault Tauziède-Espariat, Lea L Friker, Gunther Nussbaumer, Brigitte Bison, Volodia Dangouloff-Ros, Alice Métais, David Sumerauer, Josef Zamecnik, Martin Benesch, Thomas Perwein, Dannis van Vuurden, Pieter Wesseling, Andrés Morales La Madrid, Maria Luisa Garrè, Manila Antonelli, Felice Giangaspero, Torsten Pietsch, Dominik Sturm, David T W Jones, Stefan M Pfister, Yura Grabovska, Alan Mackay, Chris Jones, Jacques Grill, Yassine Ajlil, André O von Bueren, Michael Karremann, Marion Hoffmann, Christof M Kramm, Robert Kwiecien, David Castel, Gerrit H Gielen, Pascale Varlet
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引用次数: 0

Abstract

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

基于甲基化的RTK2A和RTK2B亚类的弥漫性小儿高级别胶质瘤呈现出不同的放射学和组织分子特征,包括脑胶质瘤病表型。
弥漫性儿科型高级别胶质瘤(pedHGG),H3-和IDH-野生型,包括三个主要的基于DNA甲基化的亚型:pedHGG-MYCN、pedHGG-RTK1A/B/C和pedHGG-RTK2A/B。自2017年首次描述以来,pedHGG-RTK2A/B肿瘤尚未得到全面描述,临床相关性仍难以捉摸。在最近一系列具有脑胶质瘤病(GC)生长模式的pedHGG中,观察到pedHGG-RTK2A/B(n = 18)的发生率增加。我们将 14 例经表观遗传学定义的 pedHGG-RTK2A/B 肿瘤加入到这一 GC 系列中,并提供了集中审查的放射学、组织学和分子特征。最终32例pedHGG-RTK2A/B肿瘤包括25例pedHGG-RTK2A(78%)和7例pedHGG-RTK2B(22%)。中位年龄为11.6岁(4-17岁),中位总生存期为16.0个月(10.9-28.2个月)。在新增的 11 例有影像学资料的病例中,有 7 例在诊断或随访时显示出 GC 表型。PedHGG-RTK2B肿瘤经常累及双侧丘脑(6/7,86%)。中央神经病理学检查证实,所有肿瘤均为弥漫性胶质肿瘤,两个亚类的肿瘤均具有显著的血管中心特征。大多数肿瘤(24/27,89%)弥漫表达表皮生长因子受体(EGFR),并伴有局灶性血管中心强化。PedHGG-RTK2A肿瘤缺乏OLIG2表达,而43%(3/7)的pedHGG-RTK2B肿瘤表达这种神经胶质转录因子。3/6的pedHGG-RTK2B样本(50%)出现了ATRX缺失。DNA测序(pedHGG-RTK2A:n = 18,pedHGG-RTK2B:n = 5)在两个亚类中都发现了表皮生长因子受体的改变(15/23,65%;主要是点突变)。BCOR突变(14/18,78%)、SETD2突变(7/18,39%)和hTERT启动子突变(7/19,37%)只发生在pedHGG-RTK2A肿瘤中,而pedHGG-RTK2B肿瘤则富含TP53突变(4/5,80%)。总之,pedHGG-RTK2A/B肿瘤具有高度弥漫浸润的生长模式以及特殊的放射学和组织分子特征。通过对基于甲基化的肿瘤进行全面的特征描述,为这些有害肿瘤开发特异性和有效治疗概念的机会增加了。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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