%0 Journal Article
%T CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.
%A Herrera-Pariente C
%A Bonjoch L
%A Muñoz J
%A Fernàndez G
%A Soares de Lima Y
%A Mahmood R
%A Cuatrecasas M
%A Ocaña T
%A Lopez-Prades S
%A Llargués-Sistac G
%A Domínguez-Rovira X
%A Llach J
%A Luzko I
%A Díaz-Gay M
%A Lazaro C
%A Brunet J
%A Castillo-Manzano C
%A García-González MA
%A Lanas A
%A Carrillo M
%A Hernández San Gil R
%A Quintero E
%A Sala N
%A Llort G
%A Aguilera L
%A Carot L
%A Diez-Redondo P
%A Jover R
%A Ramon Y Cajal T
%A Cubiella J
%A Castells A
%A Balaguer F
%A Bujanda L
%A Castellví-Bel S
%A Moreira L
%J Gastric Cancer
%V 27
%N 4
%D 2024 Jul 25
%M 38796558
%F 7.701
%R 10.1007/s10120-024-01504-7
%X <B>BACKGROUND: </B>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).<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.