Exome sequencing points to pathogenic ATM variants in gastric cancer
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
- Leticia Moreira
- Michele Ghidini (ORCID: https://orcid.org/0000-0001-5435-1218)
- Laura L. Koebbe (ORCID: https://orcid.org/0000-0001-9962-0741)
- Mārcis Leja (ORCID: https://orcid.org/0000-0002-0319-8855)
- Caroline Gronnier (ORCID: https://orcid.org/0000-0002-7836-8134)
- Francesca Tavano (ORCID: https://orcid.org/0000-0002-8831-7349)
- Timo Hess (ORCID: https://orcid.org/0000-0003-2778-4274)
- L. Sulpice
- Olivier Gléhen (ORCID: https://orcid.org/0000-0002-2802-4974)
- Carlo Maj (ORCID: https://orcid.org/0000-0002-9559-1725)
- Renato Cannizzaro (ORCID: https://orcid.org/0000-0002-2020-222X)
- Anna Mokrowiecka (ORCID: https://orcid.org/0000-0001-9332-8088)
- L. Bujanda
- Hakan Alakus (ORCID: https://orcid.org/0000-0002-3889-3276)
- Christiane J. Bruns (ORCID: https://orcid.org/0000-0001-6590-8181)
- S. Al-Batran
- Marino Venerito (ORCID: https://orcid.org/0000-0001-8581-0974)
- E. Malecka-Wojciesko
- Juozas Kupčinskas (ORCID: https://orcid.org/0000-0002-8760-7416)
- Núria Aragonés (ORCID: https://orcid.org/0000-0003-0983-2156)
- Thorsten Oliver Goetze (ORCID: https://orcid.org/0000-0002-8633-2748)
- I Gockel
- Anna Latiano (ORCID: https://orcid.org/0000-0003-3719-2061)
- María Asunción García-González (ORCID: https://orcid.org/0000-0002-8906-2683)
- A Lanas
- Orazio Palmieri
- Marek Majewski (ORCID: https://orcid.org/0000-0001-5363-9818)
- Stefanie Heilmann-Heimbach
- Stefania Boccia
- J Fabré
- Guillaume Piessen
- Nicole Kreuser (ORCID: https://orcid.org/0000-0002-0525-0426)
- Carina Pereira
- Maximilian Billmann
- Rui Medeiros
- Johannes Schumacher
- Lutz Hamann
- Stephan L. Haas
- Mário Dinis-Ribeiro
- Xavier B. D’Journo
- Peter Elbe
- Roberta Pastorino
- Markus M. Noethen
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Goethe University Frankfurt (DE)
- Medical University of Lublin (PL)
- Centre National de la Recherche Scientifique (FR)
- Lithuanian University of Health Sciences (LT)
- Karolinska University Hospital (SE)
- University of Bonn (DE)
- University of Trieste (IT)
- Inserm (FR)
- Philipps University of Marburg (DE)
- University of the Basque Country (ES)
- University of Cologne (DE)
- Aix-Marseille Université (FR)
- Casa Sollievo della Sofferenza (IT)
- Agostino Gemelli University Polyclinic (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Karolinska Institutet (SE)
- Centre Hospitalier Universitaire de Lille (FR)
- Humboldt-Universität zu Berlin (DE)
- Assistance Publique Hôpitaux de Marseille (FR)
- Portuguese League Against Epilepsy (PT)
- Centre Hospitalier Universitaire de Montpellier (FR)
- Riga East University Hospital (LV)
- Biogipuzkoa Health Research Institute (ES)
- Hospices Civils de Lyon (FR)
- Instituto Português de Oncologia Francisco Gentil (PT)
- Hôpital Cardiologique du Haut-Lévêque (FR)
- Medical University of Lodz (PL)
- Hôpital Pontchaillou (FR)
- University Hospital Leipzig (DE)
- Centro di Riferimento Oncologico (IT)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- University Hospital Frankfurt (DE)
- Krankenhaus Nordwest (DE)
- Hospital Clínico Universitario Lozano Blesa (ES)
- Instituto de Investigación Sanitaria Aragón (ES)
- University Hospital Magdeburg (DE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES)
- Instituto Aragonés de Ciencias de la Salud (ES)
- Centre Hospitalier Universitaire de Rennes (FR)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Istituti Ospitalieri di Cremona (IT)
- CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers (FR)
- University of Latvia (LV)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- European Journal of Human Genetics
- Published
- 2025-12-26
- DOI
- https://doi.org/10.1038/s41431-025-01994-8
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Centre Hospitalier Régional Universitaire de Montpellier
- Institut National Du Cancer
- Centre Hospitalier Universitaire de Bordeaux
- Centre hospitalier régional universitaire de Lille
- Centre Hospitalier Universitaire de Rennes
- National Cancer Institute