基于甲基化的 RTK2A 和 RTK2B 亚类的弥漫性小儿高级别神经胶质瘤呈现出不同的放射影像学和组织分子特征，包括脑胶质瘤表型。

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

机构信息

Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, 1, Rue Cabanis, 75014, Paris, France.

Inserm, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Paris, France.

出版信息

Acta Neuropathol Commun. 2024 Nov 18;12(1):176. doi: 10.1186/s40478-024-01881-1.

DOI:10.1186/s40478-024-01881-1

PMID:39558399

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11575044/

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.

摘要

弥漫性小儿型高级别神经胶质瘤（pedHGG），H3 和 IDH 野生型，包含三种主要的基于 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，临床相关性仍不清楚。在最近一系列具有脑胶质瘤病（GC）生长模式的小儿型弥漫性高级别神经胶质瘤中，pedHGG-RTK2A/B 的发生率增加（n=18）。我们在这个 GC 系列中增加了 14 个通过表观遗传定义的 pedHGG-RTK2A/B 肿瘤，并提供了中央审查的影像学、组织学和分子特征。最终的 32 例 pedHGG-RTK2A/B 肿瘤队列包括 25 例 pedHGG-RTK2A（78%）和 7 例 pedHGG-RTK2B（22%）病例。中位年龄为 11.6 岁（范围 4-17 岁），总生存期中位数为 16.0 个月（范围 10.9-28.2）。11 例新增加的病例中有 7 例在影像学上有 GC 表型，或在随访中显示 GC 表型。pedHGG-RTK2B 肿瘤表现出频繁的双侧丘脑受累（6/7，86%）。中枢神经病理学复查证实所有肿瘤均为弥漫性神经胶质瘤，两个亚类均有明显的血管中心特征。大多数肿瘤（27 例中有 24 例，89%）弥漫性表达 EGFR，伴有局灶性血管中心增强。pedHGG-RTK2A 肿瘤缺乏 OLIG2 表达，而 7/3 例（43%）pedHGG-RTK2B 表达这种神经胶质瘤转录因子。在 6 例有数据的 pedHGG-RTK2B 样本中（50%），有 3 例发生 ATRX 缺失。DNA 测序（pedHGG-RTK2A：n=18，pedHGG-RTK2B：n=5）发现两个亚类均存在 EGFR 改变（15/23，65%；主要为点突变）。BCOR（14/18，78%）、SETD2（7/18，39%）和 hTERT 启动子（7/19，37%）的突变仅发生在 pedHGG-RTK2A 肿瘤中，而 pedHGG-RTK2B 肿瘤富含 TP53 改变（4/5，80%）。总之，pedHGG-RTK2A/B 肿瘤的特点是高度弥漫浸润生长模式和特定的影像学和组织分子特征。通过全面描述基于甲基化的肿瘤，增加了为这些有害肿瘤开发特定和有效的治疗概念的机会。