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Knowledge on\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Explore\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      genotype\u2013phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>\n                      Using molecular, clinical and population data from 1308 individuals from 351\n                      <jats:italic>CTNNA1-<\/jats:italic>\n                      variant carrier families and 37\u2009428 non-carriers from European and American ancestries, we analysed genotype\u2013phenotype associations with multivariable logistic regression. With CRISPR\/Cas9\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -knockout gastric cancer (GC) cells and\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -humanised\n                      <jats:italic>Drosophila<\/jats:italic>\n                      , we assessed\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -associated loss-of-function mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -truncating carriers lose \u03b1E-catenin. These transcripts are non-functional in\n                      <jats:italic>Drosophila<\/jats:italic>\n                      , in contrast to non-truncating transcripts. DGC risk is eightfold higher in truncating, compared with non-truncating carriers. The risk of GC and lobular breast cancer (LBC) development in\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -truncating variant carriers is fivefold and eightfold lower than in\n                      <jats:italic>CDH1<\/jats:italic>\n                      pathogenic\/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -truncating and 38-fold higher in\n                      <jats:italic>CDH1<\/jats:italic>\n                      -truncating variant carriers. LBC is recurrent among\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      genetic testing produced the \u2018Porto\u2019 criteria, which increased\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -carrier families\u2019 pick-up rate by 9%, without performance loss compared with the HDGC 2020 clinical guidelines. Macular dystrophy patterned-2 was positively associated with non-truncating variants, specifically in the \u03b1E-catenin M-fragment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We provide compelling evidence supporting that\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      downregulation. We demonstrate that compared with\n                      <jats:italic>CDH1<\/jats:italic>\n                      ,\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and\/or prophylactic measures for\n                      <jats:italic>CTNNA1<\/jats:italic>\n                      -carrier individuals and families.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gutjnl-2024-334601","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T17:25:29Z","timestamp":1758821129000},"page":"872-885","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Hereditary diffuse gastric cancer spectrum associated with germline\n                    <i>CTNNA1<\/i>\n                    loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls"],"prefix":"10.1136","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-2958","authenticated-orcid":false,"given":"Silvana","family":"Lobo","sequence":"first","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"},{"name":"ICBAS -School of Medicine and Biomedical Sciences of the University of Porto, Portugal, Porto, Portugal"}]},{"given":"Alexandre","family":"Dias","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"},{"name":"ICBAS -School of Medicine and Biomedical Sciences of the University of Porto, Portugal, Porto, Portugal"}]},{"given":"Ana Maria","family":"Pedro","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"}]},{"given":"Marta","family":"Ferreira","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"},{"name":"Department of Computer Science, University of Porto Faculty of Sciences, Porto, Portugal"}]},{"given":"Andr\u00e9","family":"Pinto-Oliveira","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4292-3957","authenticated-orcid":false,"given":"Celina","family":"S\u00e3o Jos\u00e9","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"}]},{"given":"Jennifer","family":"Herrera-Mullar","sequence":"additional","affiliation":[{"name":"Ambry Genetics Corporation, Aliso Viejo, California, USA"}]},{"given":"N\u00e1dia","family":"Pinto","sequence":"additional","affiliation":[{"name":"i3S - Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, Portugal, Porto, Portugal"},{"name":"CMUP - Center of Mathematics, University of Porto, Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9146-9346","authenticated-orcid":false,"given":"Chrystelle","family":"Colas","sequence":"additional","affiliation":[{"name":"Department of Genetics, Institut Curie, Paris, France"},{"name":"INSERM U830, University of Paris, Paris, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9957-8299","authenticated-orcid":false,"given":"Robert","family":"H\u00fcneburg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany"},{"name":"National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5972-0780","authenticated-orcid":false,"given":"Jacob","family":"Nattermann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany"},{"name":"National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany"}]},{"given":"Lise","family":"Boussemart","sequence":"additional","affiliation":[{"name":"Immunology and New Concepts in ImmunoTherapy, Nantes Universit\u00e9, Nantes, France"}]},{"given":"Liselotte P","family":"van Hest","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Section Clinical Genetics, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4518-8591","authenticated-orcid":false,"given":"Leticia","family":"Moreira","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology; Institut d\u2019Investigacions Biom\u00e8diques August Pi i 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