Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin

  1. Förster, Alisa ORCID logo
  2. Brand, Frank
  3. Banan, Rouzbeh
  4. Hüneburg, Robert
  5. Weber, Christine A. M.
  6. Ewert, Wiebke
  7. Kronenberg, Jessica
  8. Previti, Christopher
  9. Elyan, Natalie
  10. Beyer, Ulrike
  11. Martens, Helge
  12. Hong, Bujung
  13. Bräsen, Jan H.
  14. Erbersdobler, Andreas
  15. Krauss, Joachim K.
  16. Stangel, Martin
  17. Samii, Amir
  18. Wolf, Stephan
  19. Preller, Matthias
  20. Aretz, Stefan
  21. Wiese, Bettina
  22. Hartmann, Christian
  23. Weber, Ruthild ORCID logo

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1000 Titel
  • Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin
1000 Autor/in
  1. Förster, Alisa |
  2. Brand, Frank |
  3. Banan, Rouzbeh |
  4. Hüneburg, Robert |
  5. Weber, Christine A. M. |
  6. Ewert, Wiebke |
  7. Kronenberg, Jessica |
  8. Previti, Christopher |
  9. Elyan, Natalie |
  10. Beyer, Ulrike |
  11. Martens, Helge |
  12. Hong, Bujung |
  13. Bräsen, Jan H. |
  14. Erbersdobler, Andreas |
  15. Krauss, Joachim K. |
  16. Stangel, Martin |
  17. Samii, Amir |
  18. Wolf, Stephan |
  19. Preller, Matthias |
  20. Aretz, Stefan |
  21. Wiese, Bettina |
  22. Hartmann, Christian |
  23. Weber, Ruthild |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-04-30
1000 Erschienen in
1000 Quellenangabe
  • 142(1):191-210
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1007/s00401-021-02307-1 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217027/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Cadherins/genetics [MeSH]
lokal Gene Knock-In Techniques [MeSH]
lokal Rats, Sprague-Dawley [MeSH]
lokal Adenoma/pathology [MeSH]
lokal Antibody Diversity [MeSH]
lokal β-catenin
lokal Genetic Variation [MeSH]
lokal Oligodendroglioma
lokal Carcinoma/genetics [MeSH]
lokal
lokal Aniline Compounds/therapeutic use [MeSH]
lokal E-cadherin
lokal Whole Genome Sequencing [MeSH]
lokal Brain Neoplasms/genetics [MeSH]
lokal Humans [MeSH]
lokal Rats [MeSH]
lokal Oligodendroglioma/pathology [MeSH]
lokal Animals [MeSH]
lokal Neoplasms, Neuroepithelial/genetics [MeSH]
lokal Protein Kinase Inhibitors/therapeutic use [MeSH]
lokal Oligodendroglioma/genetics [MeSH]
lokal Antigens, CD/genetics [MeSH]
lokal Purines/therapeutic use [MeSH]
lokal DNA, Neoplasm/genetics [MeSH]
lokal Neoplasms, Neuroepithelial/drug therapy [MeSH]
lokal Carcinoma/drug therapy [MeSH]
lokal Whole-genome sequencing
lokal HEK293 Cells [MeSH]
lokal Original Paper
lokal Adenoma/genetics [MeSH]
lokal Brain Neoplasms/drug therapy [MeSH]
lokal Familial glioma
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0002-7842-8483|https://frl.publisso.de/adhoc/uri/QnJhbmQsIEZyYW5r|https://frl.publisso.de/adhoc/uri/QmFuYW4sIFJvdXpiZWg=|https://frl.publisso.de/adhoc/uri/SMO8bmVidXJnLCBSb2JlcnQ=|https://frl.publisso.de/adhoc/uri/V2ViZXIsIENocmlzdGluZSBBLiBNLg==|https://frl.publisso.de/adhoc/uri/RXdlcnQsIFdpZWJrZQ==|https://frl.publisso.de/adhoc/uri/S3JvbmVuYmVyZywgSmVzc2ljYQ==|https://frl.publisso.de/adhoc/uri/UHJldml0aSwgQ2hyaXN0b3BoZXI=|https://frl.publisso.de/adhoc/uri/RWx5YW4sIE5hdGFsaWU=|https://frl.publisso.de/adhoc/uri/QmV5ZXIsIFVscmlrZQ==|https://frl.publisso.de/adhoc/uri/TWFydGVucywgSGVsZ2U=|https://frl.publisso.de/adhoc/uri/SG9uZywgQnVqdW5n|https://frl.publisso.de/adhoc/uri/QnLDpHNlbiwgSmFuIEgu|https://frl.publisso.de/adhoc/uri/RXJiZXJzZG9ibGVyLCBBbmRyZWFz|https://frl.publisso.de/adhoc/uri/S3JhdXNzLCBKb2FjaGltIEsu|https://frl.publisso.de/adhoc/uri/U3RhbmdlbCwgTWFydGlu|https://frl.publisso.de/adhoc/uri/U2FtaWksIEFtaXI=|https://frl.publisso.de/adhoc/uri/V29sZiwgU3RlcGhhbg==|https://frl.publisso.de/adhoc/uri/UHJlbGxlciwgTWF0dGhpYXM=|https://frl.publisso.de/adhoc/uri/QXJldHosIFN0ZWZhbg==|https://frl.publisso.de/adhoc/uri/V2llc2UsIEJldHRpbmE=|https://frl.publisso.de/adhoc/uri/SGFydG1hbm4sIENocmlzdGlhbg==|https://orcid.org/0000-0001-6610-1080
1000 Hinweis
  • DeepGreen-ID: de716f0ea20f40bab6ec70b2c8f8fcd6 ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
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1000 Erstellt am 2023-05-11T10:39:49.944+0200
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1000 Zuletzt bearbeitet 2023-10-21T03:55:40.208+0200
1000 Objekt bearb. Sat Oct 21 03:55:40 CEST 2023
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