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.

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。