Year: 2025
Type: article
Study design: Observational Study
Abstract: Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline exome sequencing data to assess the gene-based burden of loss-of-function pathogenic variants (LoF-PVs) in 471 early-onset GC cases as well as 666 GC cases from the UK Biobank (UKB), aiming to identify monogenic GC forms. In both datasets, LoF-PVs in CDH1 and ATM were enriched among GC cases. Beyond GC, ATM LoF-PVs were also enriched in UKB participants with pancreatic, oesophageal, breast, prostate, and lung cancer, though the effect size was notably high in GC. As an established disease gene for pancreatic, breast, ovarian, and prostate cancer, ATM should also be considered for genetic testing when monogenic GC is suspected. This is especially important for families in which other tumours associated with ATM PVs occur alongside GC.
Authors: Laura L. Koebbe, Timo Hess, Stephan L. Haas, Ines Gockel, Guillaume Piessen, Anna Latiano, Carina Pereira, Ewa Malecka-Wojciesko, Anna Mokrowiecka, Stefania Boccia, Marek Majewski, Hakan Alakus, Ángel Lanas, Roberta Pastorino, Thorsten Oliver Goetze, Peter Elbe, Nicole Kreuser, Orazio Palmieri, Francesca Tavano, Christiane Josephine Bruns, Olivier Glehen, Xavier B. D’Journo, Caroline Gronnier, Jean M. Fabre, Laurent Sulpice, Luis Bujanda, Leticia Moreira, Stefanie Heilmann-Heimbach, Maximilian Billmann, Markus M. Noethen, Renato Cannizzaro, Michele Ghidini, Lutz Hamann, Nuria Aragones, Mário Dinis-Ribeiro, Rui Medeiros, Salah-Eddin Al-Batran, Mārcis Leja, Juozas Kupcinskas, María A. García-González, Carlo Maj, Marino Venerito, Johannes Schumacher
Institutions: Philipps University of Marburg, Karolinska University Hospital, Karolinska Institutet, University Hospital Leipzig, Centre National de la Recherche Scientifique, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers, Casa Sollievo della Sofferenza, IPO Porto, Centro de Investigação do Instituto Português de Oncologia do Porto Francisco Gentil, RISE - Health Research Network, Medical University of Lodz, Università Cattolica del Sacro Cuore, Agostino Gemelli University Polyclinic, Medical University of Lublin, University of Cologne, Centro de Investigación Biomédica en Red, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Lozano Blesa, Instituto Aragonés de Ciencias de la Salud, Institute of Clinical Cancer Research, Krankenhaus Nordwest, Hospices Civils de Lyon, Hôpital Lyon Sud, Aix-Marseille Université, Assistance Publique Hôpitaux de Marseille, Centre Hospitalier Universitaire de Montpellier, Hôpital Pontchaillou, Centre Hospitalier Universitaire de Rennes, University of the Basque Country, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, University of Bonn, University of Trieste, Centro di Riferimento Oncologico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Azienda Socio Sanitaria Territoriale di Cremona, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Riga East University Hospital, University of Latvia, Lithuanian University of Health Sciences, Instituto de Investigación Sanitaria Aragón, University Hospital Magdeburg, Otto-von-Guericke-Universität Magdeburg
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,790
OpenAlex ID: W7117318519