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.
Exome sequencing points to pathogenic ATM variants in gastric cancer / Koebbe, Laura L.; Hess, Timo; Haas, Stephan L.; Gockel, Ines; Piessen, Guillaume; Latiano, Anna; Pereira, Carina; Malecka-Wojciesko, Ewa; Mokrowiecka, Anna; Boccia, Stefania; Majewski, Marek; Alakus, Hakan; Lanas, Ángel; Pastorino, Roberta; Goetze, Thorsten Oliver; Elbe, Peter; Kreuser, Nicole; Palmieri, Orazio; Tavano, Francesca; Bruns, Christiane Josephine; Glehen, Olivier; B. D'Journo, Xavier; Gronnier, Caroline; Fabre, Jean M.; Sulpice, Laurent; Bujanda, Luis; Moreira, Leticia; Heilmann-Heimbach, Stefanie; Billmann, Maximilian; Noethen, Markus M.; Cannizzaro, Renato; Ghidini, Michele; Hamann, Lutz; Aragones, Nuria; Dinis-Ribeiro, Mário; Medeiros, Rui; Al-Batran, Salah-Eddin; Leja, Mārcis; Kupcinskas, Juozas; García-González, María A.; Maj, Carlo; Venerito, Marino; Schumacher, Johannes. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - (2025), pp. 1-6. [Epub ahead of print] [10.1038/s41431-025-01994-8]
Exome sequencing points to pathogenic ATM variants in gastric cancer
Cannizzaro, RenatoWriting – Review & Editing
;
2025-01-01
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.Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
