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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;\u2009&lt;\u200950\u00a0years old).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, <jats:italic>CTNND1<\/jats:italic> 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 <jats:italic>CTNND1<\/jats:italic> cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed \u03b2-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Three <jats:italic>CTNND1<\/jats:italic> germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C\u2009&gt;\u2009T, p.(Pro369Ser); c.1537A\u2009&gt;\u2009G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding <jats:italic>CTNND1<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Defects in <jats:italic>CTNND1<\/jats:italic> could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, <jats:italic>CTNND1<\/jats:italic> germline variants explained 2% (3\/172) of the cases, although further studies in larger external cohorts are needed.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10120-024-01504-7","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T19:01:32Z","timestamp":1716663692000},"page":"747-759","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell 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