TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
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
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  -