Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-09-10 DOI:10.1007/s00401-024-02800-3
Lotte Stegat, Alicia Eckhardt, Antonia Gocke, Sina Neyazi, Lara Pohl, Simone Schmid, Matthias Dottermusch, Stephan Frank, Hans Pinnschmidt, Jochen Herms, Markus Glatzel, Matija Snuderl, Leonille Schweizer, Christian Thomas, Julia Neumann, Mario M. Dorostkar, Ulrich Schüller, Annika K. Wefers
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Abstract

H3 K27M-altered diffuse midline gliomas (DMGs) are highly malignant tumours that arise in the midline structures of the CNS. Most DMGs carry an H3 K27M-mutation in one of the genes encoding for histone H3. Recent studies suggested that epigenetic subgroups of DMGs can be distinguished based on alterations in the MAPK-signalling pathway, tumour localisation, mutant H3-gene, or overall survival (OS). However, as these parameters were studied individually, it is unclear how they collectively influence survival. Hence, we analysed dependencies between different parameters, to define novel epigenetic, clinically meaningful subgroups of DMGs. We collected a multifaceted cohort of 149 H3 K27M-mutant DMGs, also incorporating data of published cases. DMGs were included in the study if they could be clearly allocated to the spinal cord (n = 31; one patient with an additional sellar tumour), medulla (n = 20), pons (n = 64) or thalamus (n = 33), irrespective of further known characteristics. We then performed global genome-wide DNA methylation profiling and, for a subset, DNA sequencing and survival analyses. Unsupervised hierarchical clustering of DNA methylation data indicated two clusters of DMGs, i.e. subtypes DMG-A and DMG-B. These subtypes differed in mutational spectrum, tumour localisation, age at diagnosis and overall survival. DMG-A was enriched for DMGs with MAPK-mutations, medullary localisation and adult age. 13% of DMG-A had a methylated MGMT promoter. Contrarily, DMG-B was enriched for cases with TP53-mutations, PDGFRA-amplifications, pontine localisation and paediatric patients. In univariate analyses, the features enriched in DMG-B were associated with a poorer survival. However, all significant parameters tested were dependent on the cluster attribution, which had the largest effect on survival: DMG-A had a significantly better survival compared to DMG-B (p < 0.001). Hence, the subtype attribution based on two methylation clusters can be used to predict survival as it integrates different molecular and clinical parameters.

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综合分析揭示了H3 K27M突变弥漫中线胶质瘤的两种分子和临床不同亚型,具有预后意义
H3 K27M变异弥漫性中线胶质瘤(DMGs)是一种发生在中枢神经系统中线结构的高度恶性肿瘤。大多数弥漫性中线胶质瘤的组蛋白H3编码基因之一携带H3 K27M突变。最近的研究表明,DMG 的表观遗传亚群可根据 MAPK 信号通路、肿瘤定位、突变 H3 基因或总生存期(OS)的改变加以区分。然而,由于这些参数是单独研究的,因此尚不清楚它们如何共同影响生存。因此,我们分析了不同参数之间的依赖关系,以确定新的具有临床意义的DMGs表观遗传亚组。我们收集了149例H3 K27M突变DMG的多方面队列,同时还纳入了已发表病例的数据。如果DMG可以明确归属于脊髓(31例;其中一名患者伴有额外的鞘膜肿瘤)、延髓(20例)、脑桥(64例)或丘脑(33例),则无论其他已知特征如何,均被纳入研究。然后,我们进行了全基因组DNA甲基化分析,并对部分患者进行了DNA测序和生存分析。DNA甲基化数据的无监督分层聚类显示,DMGs有两个聚类,即DMG-A和DMG-B亚型。这两个亚型在突变谱、肿瘤定位、确诊年龄和总生存率方面存在差异。DMG-A富含MAPK突变、髓质定位和成年年龄。13%的DMG-A具有甲基化的MGMT启动子。相反,DMG-B富集于TP53突变、PDGFRA扩增、桥脑定位和儿科患者。在单变量分析中,DMG-B富集的特征与较差的生存率有关。然而,所有测试的重要参数都取决于集群归因,而集群归因对生存率的影响最大:与 DMG-B 相比,DMG-A 的生存率明显更高(p <0.001)。因此,基于两个甲基化群的亚型归因可用于预测生存率,因为它整合了不同的分子和临床参数。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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