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Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2021-04-30 , DOI: 10.1007/s00401-021-02307-1
Alisa Förster 1 , Frank Brand 1 , Rouzbeh Banan 2, 3 , Robert Hüneburg 4, 5 , Christine A M Weber 1 , Wiebke Ewert 6 , Jessica Kronenberg 7, 8, 9 , Christopher Previti 10, 11 , Natalie Elyan 1 , Ulrike Beyer 1 , Helge Martens 1 , Bujung Hong 12 , Jan H Bräsen 13 , Andreas Erbersdobler 14 , Joachim K Krauss 12 , Martin Stangel 7, 8 , Amir Samii 15 , Stephan Wolf 10 , Matthias Preller 6, 16 , Stefan Aretz 4, 17 , Bettina Wiese 12, 18 , Christian Hartmann 2 , Ruthild G Weber 1
Affiliation  

The genetic basis of brain tumor development is poorly understood. Here, leukocyte DNA of 21 patients from 15 families with ≥ 2 glioma cases each was analyzed by whole-genome or targeted sequencing. As a result, we identified two families with rare germline variants, p.(A592T) or p.(A817V), in the E-cadherin gene CDH1 that co-segregate with the tumor phenotype, consisting primarily of oligodendrogliomas, WHO grade II/III, IDH-mutant, 1p/19q-codeleted (ODs). Rare CDH1 variants, previously shown to predispose to gastric and breast cancer, were significantly overrepresented in these glioma families (13.3%) versus controls (1.7%). In 68 individuals from 28 gastric cancer families with pathogenic CDH1 germline variants, brain tumors, including a pituitary adenoma, were observed in three cases (4.4%), a significantly higher prevalence than in the general population (0.2%). Furthermore, rare CDH1 variants were identified in tumor DNA of 6/99 (6%) ODs. CDH1 expression was detected in undifferentiated and differentiating oligodendroglial cells isolated from rat brain. Functional studies using CRISPR/Cas9-mediated knock-in or stably transfected cell models demonstrated that the identified CDH1 germline variants affect cell membrane expression, cell migration and aggregation. E-cadherin ectodomain containing variant p.(A592T) had an increased intramolecular flexibility in a molecular dynamics simulation model. E-cadherin harboring intracellular variant p.(A817V) showed reduced β-catenin binding resulting in increased cytosolic and nuclear β-catenin levels reverted by treatment with the MAPK interacting serine/threonine kinase 1 inhibitor CGP 57380. Our data provide evidence for a role of deactivating CDH1 variants in the risk and tumorigenesis of neuroepithelial and epithelial brain tumors, particularly ODs, possibly via WNT/β-catenin signaling.



中文翻译:


E-钙粘蛋白基因 CDH1 中的罕见种系变异与神经上皮和上皮来源的脑肿瘤的风险相关



人们对脑肿瘤发展的遗传基础知之甚少。在这里,通过全基因组或靶向测序对来自 15 个家庭的 21 名患者的白细胞 DNA 进行了分析,这些患者的胶质瘤病例≥2 例。结果,我们在 E-钙粘蛋白基因CDH1中发现了两个具有罕见种系变异 p.(A592T) 或 p.(A817V) 的家族,它们与肿瘤表型共分离,主要由少突胶质细胞瘤组成,WHO II 级/ III,IDH 突变体,1p/19q 编码缺失 (OD)。先前显示罕见的CDH1变异易患胃癌和乳腺癌,与对照组 (1.7%) 相比,这些神经胶质瘤家族 (13.3%) 中的比例明显过高。在来自 28 个具有致病性CDH1种系变异的胃癌家族的 68 名个体中,观察到 3 例(4.4%)脑肿瘤(包括垂体腺瘤),显着高于一般人群(0.2%)的患病率。此外,在 6/99 (6%) OD 的肿瘤 DNA 中发现了罕见的CDH1变异。在从大鼠脑中分离的未分化和分化少突胶质细胞中检测到CDH1表达。使用 CRISPR/Cas9 介导的敲入或稳定转染细胞模型的功能研究表明,已鉴定的CDH1种系变异影响细胞膜表达、细胞迁移和聚集。含有变体 p.(A592T) 的 E-钙粘蛋白胞外域在分子动力学模拟模型中具有增加的分子内灵活性。含有细胞内变体 p.(A817V) 的 E-钙粘蛋白显示 β- 连环蛋白结合减少,导致胞质和核 β-连环蛋白水平增加,通过使用 MAPK 相互作用的丝氨酸/苏氨酸激酶 1 抑制剂 CGP 57380 处理可恢复。 我们的数据提供了证据,证明失活CDH1变体在神经上皮和上皮性脑肿瘤(尤其是 OD)的风险和肿瘤发生中的作用,可能是通过 WNT/β-连环蛋白信号传导实现的。

更新日期:2021-04-30
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