CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.

Autor: Herrera-Pariente C; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Bonjoch L; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Muñoz J; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Fernàndez G; Hospital Sant Joan de Déu, CIBERER, 08950, Barcelona, Spain., Soares de Lima Y; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Mahmood R; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Cuatrecasas M; Pathology, Hospital Clínic, FRCB-IDIBAPS, CIBEREHD, 08036, Barcelona, Spain., Ocaña T; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Lopez-Prades S; Pathology, Hospital Clínic, FRCB-IDIBAPS, CIBEREHD, 08036, Barcelona, Spain., Llargués-Sistac G; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Domínguez-Rovira X; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Llach J; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Luzko I; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Díaz-Gay M; Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, UC San Diego, La Jolla, San Diego, CA, 92093, USA., Lazaro C; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, 08908, Barcelona, Spain., Brunet J; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, 08908, Barcelona, Spain.; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGI, 17190, Girona, Spain., Castillo-Manzano C; Hereditary Cancer Program, Catalan Institute of Oncology, 08916, Badalona, Spain., García-González MA; Instituto de Investigación Sanitaria Aragón, Instituto Aragonés de Ciencias de La Salud, CIBEREHD, 50009, Zaragoza, Spain., Lanas A; Instituto de Investigación Sanitaria Aragón, Instituto Aragonés de Ciencias de La Salud, CIBEREHD, 50009, Zaragoza, Spain.; Gastroenterology, Hospital Clínico Universitario de Zaragoza, Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, CIBEREHD, 50009, Zaragoza, Spain., Carrillo M; Gastroenterology, Centro de Investigación Biomédica de Canarias (CIBICAN), Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38320, Santa Cruz de Tenerife, Spain., Hernández San Gil R; Department of Medical Oncology, Hospital Universitario de Canarias, 38320, Tenerife, Spain., Quintero E; Gastroenterology, Centro de Investigación Biomédica de Canarias (CIBICAN), Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB), Universidad de La Laguna, 38320, Santa Cruz de Tenerife, Spain., Sala N; Unit of Nutrition and Cancer, Translational Research Laboratory, Catalan Institute of Oncology (ICO) and Bellvitge Biomedical Research Institute (IDIBELL), 08908, Barcelona, Spain., Llort G; Medical Oncology, Parc Taulí University Hospital, 08208, Sabadell, Spain., Aguilera L; Gastroenterology, Vall d'Hebron Research Institute, 08035, Barcelona, Spain., Carot L; Gastroenterology, Hospital del Mar, 08003, Barcelona, Spain., Diez-Redondo P; Hospital Universitario Río Hortega, 47012, Valladolid, Spain., Jover R; Gastroenterology, Departamento de Medicina Clínica, Hospital General Universitario Dr. Balmis, Instituto de Investigación Sanitaria ISABIAL, Universidad Miguel Hernández, 03010, Alicante, Spain., Ramon Y Cajal T; Medical Oncology, Santa Creu I Sant Pau Hospital, 08041, Barcelona, Spain., Cubiella J; Gastroenterology, Complexo Hospitalario de Ourense, CIBEREHD, 32005, Ourense, Spain., Castells A; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Balaguer F; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Bujanda L; Department of Hepatology and Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Biodonostia Health Research Institute - Donostia University Hospital, Universidad del País Vasco (UPV/EHU), 20014, San Sebastián, Spain., Castellví-Bel S; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain., Moreira L; Gastroenterology, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer (FRCB-IDIBAPS), CIBEREHD, Universitat de Barcelona, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain. lmoreira@clinic.cat.; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain. lmoreira@clinic.cat.
Jazyk: angličtina
Zdroj: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association [Gastric Cancer] 2024 Jul; Vol. 27 (4), pp. 747-759. Date of Electronic Publication: 2024 May 25.
DOI: 10.1007/s10120-024-01504-7
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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