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

Herrera-Pariente, Cristina ; Bonjoch, Laia ; Muñoz, Jenifer ; Fernàndez, Guerau ; Soares de Lima, Yasmin ; Mahmood, Romesa ; Cuatrecasas, Miriam ; Ocaña, Teresa ; Lopez-Prades, Sandra ; Llargués-Sistac, Gemma ; Domínguez-Rovira, Xavier ; Llach, Joan ; Luzko, Irina ; Díaz-Gay, Marcos ; Lazaro, Conxi ; Brunet, Joan ; Castillo-Manzano, Carmen ; García-González, María Asunción ; Lanas, Ángel (Universidad de Zaragoza) ; Carrillo, Marta ; Hernández San Gil, Raquel ; Quintero, Enrique ; Sala, Nuria ; Llort, Gemma ; Aguilera, Lara ; Carot, Laura ; Diez-Redondo, Pilar ; Jover, Rodrigo ; Ramon y Cajal, Teresa ; Cubiella, Joaquín ; Castells, Antoni ; Balaguer, Francesc ; Bujanda, Luis ; Castellví-Bel, Sergi ; Moreira, Leticia

Resumen: 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 fndings 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 identifed 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.

Idioma: Inglés

DOI: 10.1007/s10120-024-01504-7

Año: 2024

Publicado en: Gastric Cancer 27, 4 (2024), 747-759
ISSN: 1436-3291

Financiación: info:eu-repo/grantAgreement/EC/HORIZON EUROPE/101079217/EU/TWINNING FOR A EUROPEAN CONSORTIUM OF RECTAL CANCER RESEARCH INSTITUTIONS THROUGH STEPPING UP SCIENTIFIC, TECHNOLOGICAL AND INNOVATION EXCELLENCE OF IORS/STEPUPIORS
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI16-00599
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI20-00113
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI21-00333
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI22-00537

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)