Aggressive human MenG C meningiomas have a molecular counterpart in canines.
Aggressive human MenG C meningiomas have a molecular counterpart in canines.
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侵袭性人类 MenG C 脑膜瘤在犬科动物中具有分子对应物。
DOI：
10.1007/s00401-024-02692-3
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发表时间：
2024
影响因子：
12.7
通讯作者：
Patel,AkashJ
中科院分区：
文献类型：
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作者：
Harmanci,AkdesS;Boudreau,Beth;Lau,Sean;HosseingholiNouri,Shervin;Mandel,JacobJ;Lu,Hsiang-Chih;Harmanci,ArifO;Klisch,TiemoJ;Levine,JonathanM;Patel,AkashJ
脑膜瘤不仅是人类最常见的原发性颅内肿瘤，也是家庭宠物，如猫和狗[9，10，12]。我们首先报道了人类脑膜瘤根据其mRNA表达特征形成三个生物学上不同的组[6]。这些组-MenG A、B和C-可以使用RNA测序（RNA-seq）、DNA甲基化或CNV分析来鉴定[1，2]，并且已经被独立地验证[3，5]。然而，只有MenG C肿瘤表现为侵袭性，没有有效的治疗方法，并且尽管用手术和/或放射治疗仍会复发。这些肿瘤可以通过四个标志与其他两组区分开来：（1）染色体不稳定性，（2）细胞增殖增加，（3）DREAM-MuvB复合物共调节因子及其靶点表达增加，以及（4）启动子超甲基化[1-6]。理解脑膜瘤生物学的一个主要障碍是缺乏可靠的模型，因为原代细胞在7-9代后变得衰老，并且难以建立患者来源的颅内异种移植物[13]。鉴于犬脑膜瘤非常常见，并且与人类脑膜瘤有显著的组织学重叠[7，11]，我们试图确定人类MenG C是否与犬相似。我们使用RNA测序测量了来自27个犬品种的62个组织学证实的犬脑膜瘤的基因表达（方法见在线资源，补充表1）。在我们的队列中，犬脑膜瘤在组织学上与人类脑膜瘤非常相似（补充图S1）。采用两种不同的聚类方法，特别是主成分分析（PCA）和共有聚类，对表达数据进行无监督分析，鉴定了狗脑膜瘤内的三个不同的转录组，类似于人脑膜瘤的基于表达的聚类（图1a-c）。这三类可以从基因表达谱中辨别出来（图1d），在PCA图中离散分组（图1 e）。我们探讨了其中一个是否对应于人类MenG C组。脑膜瘤生物学最常见的驱动因素是Merlin的丢失，Merlin是由位于人类22号染色体和犬26号染色体上的NF 2基因编码的蛋白质。在我们的研究队列中，我们没有观察到26号染色体上的任何丢失或NF 2基因表达的显著变化。
Meningiomas are not only the most common primary intracranial tumor in humans, but also in household pets, such as cats and dogs [9, 10, 12]. We first reported that human meningiomas form three biologically distinct groups based on their mRNA expression signatures [6]. These groups—MenG A, B and C—can be identified using RNA-sequencing (RNA-seq), DNA methylation, or CNV analysis [1, 2] and have been validated independently [3, 5]. However, only MenG C tumors behave aggressively, have no effective treatment, and recur despite treatment with surgery and/or radiation. These tumors can be differentiated from the other two groups by four hallmarks:(1) chromosomal instability,(2) increased cell proliferation,(3) increased expression of the DREAM-MuvB complex co-regulators and its targets, and (4) promoter hypermethylation [1–6]. One major barrier in understanding meningioma biology has been the lack of reliable models, as primary cells become senescent after 7–9 passages and patient-derived intracranial xenografts are difficult to establish [13]. Given that canine meningiomas are exceedingly common and have significant histologic overlap with human meningiomas [7, 11], we sought to determine if the human MenG C has a canine parallel.We measured gene expression in 62 histologically confirmed canine meningiomas from 27 dog breeds using RNA-sequencing (see online resources for methods, Supplementary Table 1). In our cohort, canine meningiomas strongly resembled human meningiomas histologically (Supplemental Fig. S1). Unsupervised analysis of expression data employing two distinct clustering methods, specifically principal component analysis (PCA) and consensus clustering, identified three distinct transcriptional groups within dog meningiomas similar to expression-based clustering of human meningiomas (Fig. 1 a–c). The three classes can be discerned from the gene expression profiles (Fig. 1 d), are discretely grouped in the PCA plot (Fig. 1 e). We explored whether one of these corresponds to the human MenG C group. The most common driver of meningioma biology is loss of Merlin, the protein encoded by the NF2 gene located on human chromosome 22 and canine chromosome 26. In our study cohort, we did not observe any losses on chromosome 26 or significant variations in NF2 gene expression.