TY - JOUR U1 - Wissenschaftlicher Artikel A1 - Förster, Alisa A1 - Brand, Frank A1 - Banan, Rouzbeh A1 - Hüneburg, Robert A1 - Weber, Christine A. M. A1 - Ewert, Wiebke A1 - Kronenberg, Jessica A1 - Previti, Christopher A1 - Elyan, Natalie A1 - Beyer, Ulrike A1 - Martens, Helge A1 - Hong, Bujung A1 - Bräsen, Jan H. A1 - Erbersdobler, Andreas A1 - Krauss, Joachim K. A1 - Stangel, Martin A1 - Samii, Amir A1 - Wolf, Stephan A1 - Preller, Matthias A1 - Aretz, Stefan A1 - Wiese, Bettina A1 - Hartmann, Christian A1 - Weber, Ruthild G. T1 - Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin JF - Acta Neuropathologica N2 - 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. KW - Familial glioma KW - Oligodendroglioma KW - Whole-genome sequencing KW - CDH1 KW - E-cadherin KW - β-catenin Y1 - 2021 UN - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-53988 SN - 0001-6322 SS - 0001-6322 U6 - https://doi.org/10.1007/s00401-021-02307-1 DO - https://doi.org/10.1007/s00401-021-02307-1 PM - 33929593 VL - 142 IS - 1 SP - 191 EP - 210 PB - Springer CY - New York, NY, USA ER -