GOPC:ROS1 and other ROS1 fusions represent a rare but recurrent drug target in a variety of glioma types

  1. Sievers, Philipp ORCID logo
  2. Stichel, Damian
  3. Sill, Martin
  4. Schrimpf, Daniel
  5. Sturm, Dominik
  6. Selt, Florian
  7. Ecker, Jonas
  8. Kazdal, Daniel
  9. Miele, Evelina
  10. Kranendonk, Mariëtte E. G.
  11. Tops, Bastiaan B. J.
  12. Kohlhof-Meinecke, Patricia
  13. Beschorner, Rudi
  14. Kramm, Christof M.
  15. Hasselblatt, Martin
  16. Reifenberger, Guido
  17. Capper, David
  18. Wesseling, Pieter
  19. Stenzinger, Albrecht
  20. Milde, Till
  21. Korshunov, Andrey
  22. Witt, Olaf
  23. Pfister, Stefan M.
  24. Wick, Wolfgang
  25. von Deimling, Andreas
  26. Jones, David T. W.
  27. Sahm, Felix ORCID logo

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1000 Titel
  • GOPC:ROS1 and other ROS1 fusions represent a rare but recurrent drug target in a variety of glioma types
1000 Autor/in
  1. Sievers, Philipp |
  2. Stichel, Damian |
  3. Sill, Martin |
  4. Schrimpf, Daniel |
  5. Sturm, Dominik |
  6. Selt, Florian |
  7. Ecker, Jonas |
  8. Kazdal, Daniel |
  9. Miele, Evelina |
  10. Kranendonk, Mariëtte E. G. |
  11. Tops, Bastiaan B. J. |
  12. Kohlhof-Meinecke, Patricia |
  13. Beschorner, Rudi |
  14. Kramm, Christof M. |
  15. Hasselblatt, Martin |
  16. Reifenberger, Guido |
  17. Capper, David |
  18. Wesseling, Pieter |
  19. Stenzinger, Albrecht |
  20. Milde, Till |
  21. Korshunov, Andrey |
  22. Witt, Olaf |
  23. Pfister, Stefan M. |
  24. Wick, Wolfgang |
  25. von Deimling, Andreas |
  26. Jones, David T. W. |
  27. Sahm, Felix |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-09-18
1000 Erschienen in
1000 Quellenangabe
  • 142(6):1065-1069
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1007/s00401-021-02369-1 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568855/ |
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 Brain Neoplasms/genetics [MeSH]
lokal Golgi Matrix Proteins/genetics [MeSH]
lokal Humans [MeSH]
lokal Oncogene Proteins, Fusion/genetics [MeSH]
lokal Protein-Tyrosine Kinases/genetics [MeSH]
lokal Oncogene Fusion/genetics [MeSH]
lokal Molecular Targeted Therapy [MeSH]
lokal Adaptor Proteins, Signal Transducing/genetics [MeSH]
lokal Glioma/genetics [MeSH]
lokal Pathology
lokal Proto-Oncogene Proteins/genetics [MeSH]
lokal Neurosciences
lokal Correspondence
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0003-3237-6021|https://frl.publisso.de/adhoc/uri/U3RpY2hlbCwgRGFtaWFu|https://frl.publisso.de/adhoc/uri/U2lsbCwgTWFydGlu|https://frl.publisso.de/adhoc/uri/U2NocmltcGYsIERhbmllbA==|https://frl.publisso.de/adhoc/uri/U3R1cm0sIERvbWluaWs=|https://frl.publisso.de/adhoc/uri/U2VsdCwgRmxvcmlhbg==|https://frl.publisso.de/adhoc/uri/RWNrZXIsIEpvbmFz|https://frl.publisso.de/adhoc/uri/S2F6ZGFsLCBEYW5pZWw=|https://frl.publisso.de/adhoc/uri/TWllbGUsIEV2ZWxpbmE=|https://frl.publisso.de/adhoc/uri/S3JhbmVuZG9uaywgTWFyacOrdHRlIEUuIEcu|https://frl.publisso.de/adhoc/uri/VG9wcywgQmFzdGlhYW4gQi4gSi4=|https://frl.publisso.de/adhoc/uri/S29obGhvZi1NZWluZWNrZSwgUGF0cmljaWE=|https://frl.publisso.de/adhoc/uri/QmVzY2hvcm5lciwgUnVkaQ==|https://frl.publisso.de/adhoc/uri/S3JhbW0sIENocmlzdG9mIE0u|https://frl.publisso.de/adhoc/uri/SGFzc2VsYmxhdHQsIE1hcnRpbg==|https://frl.publisso.de/adhoc/uri/UmVpZmVuYmVyZ2VyLCBHdWlkbw==|https://frl.publisso.de/adhoc/uri/Q2FwcGVyLCBEYXZpZA==|https://frl.publisso.de/adhoc/uri/V2Vzc2VsaW5nLCBQaWV0ZXI=|https://frl.publisso.de/adhoc/uri/U3RlbnppbmdlciwgQWxicmVjaHQ=|https://frl.publisso.de/adhoc/uri/TWlsZGUsIFRpbGw=|https://frl.publisso.de/adhoc/uri/S29yc2h1bm92LCBBbmRyZXk=|https://frl.publisso.de/adhoc/uri/V2l0dCwgT2xhZg==|https://frl.publisso.de/adhoc/uri/UGZpc3RlciwgU3RlZmFuIE0u|https://frl.publisso.de/adhoc/uri/V2ljaywgV29sZmdhbmc=|https://frl.publisso.de/adhoc/uri/dm9uIERlaW1saW5nLCBBbmRyZWFz|https://frl.publisso.de/adhoc/uri/Sm9uZXMsIERhdmlkIFQuIFcu|https://orcid.org/0000-0001-5441-1962
1000 Hinweis
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1000 Erstellt am 2023-05-11T10:27:27.369+0200
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1000 Zuletzt bearbeitet Sat Oct 14 15:31:17 CEST 2023
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