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

• DOI: 10.1007/s10120-024-01504-7
• Publication Date: 2024-05-25T19:01:32Z
• Authors: Cristina Herrera-...; Laia Bonjoch; Jenifer Muñoz; Guerau Fernàndez; Yasmin Soares de ...; Romesa Mahmood; Miriam Cuatrecasas; Teresa Ocaña; Sandra Lopez-Prades; Gemma Llargués-Si...; Xavier Domínguez-...; Joan Llach; Irina Luzko; Marcos Díaz-Gay; Conxi Lazaro; Joan Brunet; Carmen Castillo-M...; María Asunción Ga...; Angel Lanas; Marta Carrillo; Raquel Hernández ...; Enrique Quintero; Nuria Sala; Gemma Llort; Lara Aguilera; Laura Carot; Pilar Diez-Redondo; Rodrigo Jover; Teresa Ramon y Cajal; Joaquín Cubiella; Antoni Castells; Francesc Balaguer; Luis Bujanda; Sergi Castellví-Bel; Leticia Moreira
• Keywords: CDH1; Surgical oncology; Exome

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