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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

  • 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.

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Document Type:Article
Author:Alisa Förster, Frank Brand, Rouzbeh Banan, Robert Hüneburg, Christine A. M. Weber, Wiebke Ewert, Jessica Kronenberg, Christopher Previti, Natalie Elyan, Ulrike Beyer, Helge Martens, Bujung Hong, Jan H. Bräsen, Andreas Erbersdobler, Joachim K. Krauss, Martin Stangel, Amir Samii, Stephan Wolf, Matthias Preller, Stefan Aretz, Bettina Wiese, Christian Hartmann, Ruthild G. Weber
Parent Title (English):Acta Neuropathologica
First Page:191
Last Page:210
Place of publication:New York, NY, USA
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2021/04/30
Copyright:© The Author(s) 2021.
Funding:Open Access funding enabled and organized by Projekt DEAL. This study was supported by the Wilhelm Sander-Stiftung (grant no. 2018.097.1 to RGW).
Keyword:CDH1; E-cadherin; Familial glioma; Oligodendroglioma; Whole-genome sequencing; β-catenin
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für Technik, Ressourcenschonung und Energieeffizienz (TREE)
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2021/05/01
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International