{
  "abstract": "Background Diffuse gastric cancer (DGC) is the most common manifestation in germline CTNNA1 variant carriers, with one study estimating a 49–57% lifetime risk by age 80. Knowledge on CTNNA1-associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce.Objective Explore CTNNA1 genotype–phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers.Design Using molecular, clinical and population data from 1308 individuals from 351 CTNNA1-variant carrier families and 37 428 non-carriers from European and American ancestries, we analysed genotype–phenotype associations with multivariable logistic regression. With CRISPR/Cas9 CTNNA1-knockout gastric cancer (GC) cells and CTNNA1-humanised Drosophila, we assessed CTNNA1-associated loss-of-function mechanisms.Results CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin. These transcripts are non-functional in Drosophila, 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 CTNNA1-truncating variant carriers is fivefold and eightfold lower than in CDH1 pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers. LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for CTNNA1 genetic testing produced the ‘Porto’ criteria, which increased CTNNA1-carrier families’ 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 αE-catenin M-fragment.Conclusion We provide compelling evidence supporting that CTNNA1-truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to CTNNA1 downregulation. We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for CTNNA1-carrier individuals and families.",
  "authors": [
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "ICBAS -School of Medicine and Biomedical Sciences of the University of Porto, Portugal, Porto, Portugal"
      ],
      "name": "Silvana Lobo"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "ICBAS -School of Medicine and Biomedical Sciences of the University of Porto, Portugal, Porto, Portugal"
      ],
      "name": "Alexandre Dias"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal"
      ],
      "name": "Ana Maria Pedro"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "Department of Computer Science, University of Porto Faculty of Sciences, Porto, Portugal"
      ],
      "name": "Marta Ferreira"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal"
      ],
      "name": "André Pinto-Oliveira"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal"
      ],
      "name": "Celina São José"
    },
    {
      "affiliations": [
        "Ambry Genetics Corporation, Aliso Viejo, California, USA"
      ],
      "name": "Jennifer Herrera-Mullar"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "CMUP - Center of Mathematics, University of Porto, Porto, Portugal"
      ],
      "name": "Nádia Pinto"
    },
    {
      "affiliations": [
        "Department of Genetics, Institut Curie, Paris, France",
        "INSERM U830, University of Paris, Paris, France"
      ],
      "name": "Chrystelle Colas"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany",
        "National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany"
      ],
      "name": "Robert Hüneburg"
    },
    {
      "affiliations": [
        "Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany",
        "National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany"
      ],
      "name": "Jacob Nattermann"
    },
    {
      "affiliations": [
        "Immunology and New Concepts in ImmunoTherapy, Nantes Université, Nantes, France"
      ],
      "name": "Lise Boussemart"
    },
    {
      "affiliations": [
        "Department of Human Genetics, Section Clinical Genetics, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Liselotte P van Hest"
    },
    {
      "affiliations": [
        "Department of Gastroenterology",
        "Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)",
        "Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clinic de Barcelona, Barcelona, Spain",
        "Facultat de Medicina i Ciencies de la Salut, Universitat de Barcelona, Barcelona, Spain"
      ],
      "name": "Leticia Moreira"
    },
    {
      "affiliations": [
        "Ambry Genetics Corporation, Aliso Viejo, California, USA"
      ],
      "name": "Carolyn Horton"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Dana Farengo Clark"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria"
      ],
      "name": "Sigrid Tinschert"
    },
    {
      "affiliations": [
        "Department of Genetics, Institut Curie, Paris, France"
      ],
      "name": "Lisa Golmard"
    },
    {
      "affiliations": [
        "National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany",
        "Institute of Human Genetics, University of Bonn Medical Faculty, Bonn, Germany"
      ],
      "name": "Isabel Spier"
    },
    {
      "affiliations": [
        "Hereditary Cancer Genetics Group, Medical Oncology Department, Vall d’Hebron Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain"
      ],
      "name": "Adriá López-Fernández"
    },
    {
      "affiliations": [
        "Medical Genetics Unit, Paediatric Hospital, Coimbra Hospital and University Centre, Coimbra, Portugal"
      ],
      "name": "Daniela Oliveira"
    },
    {
      "affiliations": [
        "Equipe Instabilité Des Microsatellites Et Cancer, Centre de Recherche Saint Antoine, Sorbonne Université, Paris, France"
      ],
      "name": "Magali SVRCEK"
    },
    {
      "affiliations": [
        "Sorbonne Université, Laboratoire D’anatomie Et Cytologie Pathologiques, Hôpital Saint-Antoine, Paris, France"
      ],
      "name": "Pierre Bourgoin"
    },
    {
      "affiliations": [
        "Département de Génétique médicale, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France"
      ],
      "name": "Florence Coulet"
    },
    {
      "affiliations": [
        "Department of Genetics, Institut Curie, Paris, France",
        "Université Paris Sciences et Lettres, Paris, France"
      ],
      "name": "Hélène Delhomelle"
    },
    {
      "affiliations": [
        "Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA"
      ],
      "name": "Jeremy Davis"
    },
    {
      "affiliations": [
        "Institut für Klinische Genetik, Universitätsklinikum CarlGustav Carus, Dresden, Germany"
      ],
      "name": "Birthe Zäncker"
    },
    {
      "affiliations": [
        "Hereditary Cancer Program, Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell) Program",
        "Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Catalan Institute of Oncology, L’Hospitalet de Llobregat, Spain",
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain"
      ],
      "name": "Conxi Lazaro"
    },
    {
      "affiliations": [
        "Cancer Genetics Group and Department of Laboratory Genetics, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Francisco Gentil Portuguese Institute for Oncology of Porto, Porto, Portugal",
        "Doctoral Programme in Biomedical Sciences, University of Porto Institute of Biomedical Sciences Abel Salazar, Porto, Portugal"
      ],
      "name": "Joana Guerra"
    },
    {
      "affiliations": [
        "ULSBraga - Unidade Local de Saúde de Braga, Braga, Portugal"
      ],
      "name": "Maria L Almeida"
    },
    {
      "affiliations": [
        "Genetic Counseling Unit-Medical Oncology Department, Cruces University Hospital, Barakaldo, Spain"
      ],
      "name": "Sergio Carrera"
    },
    {
      "affiliations": [
        "Medical Genomics Unit, Cancer Center",
        "Laboratory of Advanced Therapies for Pediatric Solid Tumors, Cancer Division, University Clinic of Navarra, Pamplona, Spain",
        "A701 - Advanced Therapies for Pediatric Solid Tumors, IdiSNA, Pamplona, Spain"
      ],
      "name": "Ana Patiño"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Erasmus MC Cancer Institute, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands"
      ],
      "name": "Paul Gundlach"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition Service, Department of Subspecialty Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA",
        "Cornell University Weill Cornell Medicine, New York, New York, USA"
      ],
      "name": "Monika Laszkowska"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Vivian E Strong"
    },
    {
      "affiliations": [
        "ICBAS -School of Medicine and Biomedical Sciences of the University of Porto, Portugal, Porto, Portugal",
        "Cancer Genetics Group and Department of Laboratory Genetics, Research Center of IPO Porto (CI-IPOP)/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Francisco Gentil Portuguese Institute for Oncology of Porto, Porto, Portugal"
      ],
      "name": "Manuel R Teixeira"
    },
    {
      "affiliations": [
        "Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia, Canada"
      ],
      "name": "Intan Schrader"
    },
    {
      "affiliations": [
        "Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany"
      ],
      "name": "Verena Steinke-Lange"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "Department of Pathology, Unidade Local de Saúde de São João, Porto, Portugal",
        "FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal"
      ],
      "name": "Irene Gullo"
    },
    {
      "affiliations": [
        "Medical Genetics Unit, Paediatric Hospital, Coimbra Hospital and University Centre, Coimbra, Portugal"
      ],
      "name": "Sérgio Sousa"
    },
    {
      "affiliations": [
        "Serviço de Cirurgia Geral, Unidade Local de Saúde São João, Porto, Portugal"
      ],
      "name": "Manuela Batista"
    },
    {
      "affiliations": [
        "National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany",
        "Institute of Human Genetics, University of Bonn Medical Faculty, Bonn, Germany"
      ],
      "name": "Stefan Aretz"
    },
    {
      "affiliations": [
        "Hereditary Cancer Genetics Group, Medical Oncology Department, Vall d’Hebron Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain",
        "Universitat Autònoma de Barcelona, Barcelona, Spain"
      ],
      "name": "Judith Balmaña"
    },
    {
      "affiliations": [
        "Zane Cohen Centre, Sinai Health System, Toronto, Ontario, Canada"
      ],
      "name": "Melyssa Aronson"
    },
    {
      "affiliations": [
        "Cancer Genetics Departament, Barretos Cancer Hospital, Barretos, Brazil"
      ],
      "name": "Augusto Perazzolo Antoniazzi"
    },
    {
      "affiliations": [
        "Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil",
        "Department of Genetics, Brazilian National Cancer Institute, Rio de Janeiro, Brazil"
      ],
      "name": "Edenir I Palmero"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Paul Mansfield"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Lizet E van der Kolk"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Annemieke Cats"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands"
      ],
      "name": "Jolanda M van Dieren"
    },
    {
      "affiliations": [
        "Department of Gastroenterology",
        "Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)",
        "Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clinic de Barcelona, Barcelona, Spain"
      ],
      "name": "Sergi Castellví-Bel"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Bryson Katona"
    },
    {
      "affiliations": [
        "Ambry Genetics Corporation, Aliso Viejo, California, USA"
      ],
      "name": "Rachid Karam"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal"
      ],
      "name": "Paulo S Pereira"
    },
    {
      "affiliations": [
        "Département de Génétique médicale, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France"
      ],
      "name": "Patrick R Benusiglio"
    },
    {
      "affiliations": [
        "i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal, Porto, Portugal",
        "FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal",
        "IPATIMUP - Institute of Pathology and Molecular Immunology of the University of Porto, Porto, Portugal"
      ],
      "name": "Carla Oliveira"
    }
  ],
  "title": "Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls",
  "uid": "cbf12fad-48f7-5a22-a249-7823bb7c023f"
}