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García-González M.a.Author

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September 27, 2024
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CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions

Publicated to:Gastric Cancer. 27 (4): 747-759 - 2024-07-01 27(4), DOI: 10.1007/s10120-024-01504-7

Authors: Herrera-Pariente C; Bonjoch L; Muñoz J; Fernàndez G; Soares de Lima Y; Mahmood R; Cuatrecasas M; Ocaña T; Lopez-Prades S; Llargués-Sistac G; Domínguez-Rovira X; Llach J; Luzko I; Díaz-Gay M; Lazaro C; Brunet J; Castillo-Manzano C; García-González MA; Lanas A; Carrillo M; Hernández San Gil R; Quintero E; Sala N; Llort G; Aguilera L; Carot L; Diez-Redondo P; Jover R; Ramon y Cajal T; Cubiella J; Castells A; Balaguer F; Bujanda L; Castellví-Bel S; Moreira L

Affiliations

Biodonostia Health Research Institute - Author
Centro de Investigación Biomédica en Red de Cáncer - Author
Centro de Investigación Biomédica en Red de Cáncer; Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Author
Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas - Author
CIBEReHD - Author
Hospital de la Santa Creu i Sant Pau - Author
Hospital del Mar - Author
Hospital General Universitario de Alicante - Author
Hospital Sant Joan de Déu Barcelona - Author
Hospital Universitario de Canarias - Author
Hospital Universitario Rio Hortega - Author
Institute Catala Oncologia - Author
Instituto de Investigación Sanitaria Aragón (IISA) - Author
Instituto de Investigación Sanitaria Aragón (IISA); Hospital Clinico Universitario Lozano Blesa - Author
Moores Cancer Center - Author
Parc Taulí University Hospital - Author
Universitat de Barcelona - Author
Universitat de Barcelona; Universitat de Barcelona - Author
Vall d'Hebron Institut de Recerca - Author
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Abstract

Background: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). Methods: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. Results: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. Conclusions: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

Keywords

Cell adhesionDelta cateninEarly-onset diseaseGenetic predisposition to diseaseStomach neoplasms

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Gastric Cancer due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 51/322, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-07-04:

  • Scopus: 1

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-04:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 9.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 16 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 8.
  • The number of mentions on the social network X (formerly Twitter): 11 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.