复发性金刚瘤性颅咽管瘤表现出MAPK通路激活、克隆进化和罕见的TP53缺失介导的恶性进展。

IF 6.2 2区 医学 Q1 NEUROSCIENCES
John R Apps, Jose Mario Gonzalez-Meljem, Romain Guiho, Jessica C Pickles, Eric Prince, Edward Schwalbe, Nikhil Joshi, Thomas J Stone, Olumide Ogunbiyi, Jane Chalker, Akang Bassey, Georg Otto, Rosalind Davies, Debbie Hughes, Sebastian Brandner, Enrica Tan, Victoria Lee, Caroline Hayhurst, Cassie Kline, Sergi Castellano, Todd Hankinson, Timo Deutschbein, Thomas S Jacques, Juan Pedro Martinez-Barbera
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引用次数: 0

摘要

金刚瘤(ACP)和乳头状(PCP)这两种类型的颅咽管瘤是儿童和成人的临床相关肿瘤。虽然原发性颅咽管瘤的生物学特性已开始被揭示,但人们对其复发的生物学特性却知之甚少。为了填补这一知识空白,我们通过甲基化阵列、RNA 测序和 pERK1/2 免疫组织化学方法分析了一组配对的原发性和复发性样本(32 个样本来自 14 例 ACP 和 4 例 PCP)。我们发现在 6 例 ACP 复发病例中存在拷贝数改变和克隆演化,对儿童脑肿瘤网络的其他全基因组测序数据进行分析后证实,至少有 7/67 例 ACP 病例存在染色体臂拷贝数改变。MAPK/ERK 通路的激活是以前在原发性 ACP 中显示的特征,除一例复发性 ACP 病例外,在其他所有 ACP 病例中均可观察到这一特征。唯一没有 MAPK 激活的 ACP 是一个复发性恶性人类颅咽管瘤的侵袭性病例,该病例携带 CTNNB1 突变和 TP53 缺失。为了支持 TP53 突变的功能性作用,我们展示了在小鼠 ACP 模型中,Trp53 缺失会导致侵袭性肿瘤和小鼠存活率降低。最后,我们分析了肿瘤免疫浸润的特征,发现 ACP 和 PCP 的细胞组成和空间分布存在差异。这些分析共同揭示了对复发性颅咽管瘤的新认识,并提供了临床前证据,支持在针对复发性 ACP 的临床试验中评估 MAPK 通路抑制剂和免疫调节方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

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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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