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Hereditary diffuse gastric cancer spectrum associated with germline loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls.

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Authors: Silvana Lobo, Alexandre Dias, Ana Maria Pedro, Marta Ferreira, André Pinto-Oliveira, Celina São José, Jennifer Herrera-Mullar, Nádia Pinto, Chrystelle Colas, Robert Hüneburg, Jacob Nattermann, Lise Boussemart, Liselotte P van Hest, Leticia Moreira, Carolyn Horton, Dana Farengo Clark, Sigrid Tinschert, Lisa Golmard, Isabel Spier, Adriá López-Fernández, Daniela Oliveira, Magali Svrcek, Pierre Bourgoin, Florence Coulet, Hélène Delhomelle, Jeremy Davis, Birthe Zäncker, Conxi Lazaro, Joana Guerra, Maria L Almeida, Sergio Carrera, Ana Patiño, Paul Gundlach, Monika Laszkowska, Vivian E Strong, Manuel R Teixeira, Intan Schrader, Verena Steinke-Lange, Irene Gullo, Sérgio Sousa, Manuela Batista, Stefan Aretz, Judith Balmaña, Melyssa Aronson, Augusto Perazzolo Antoniazzi, Edenir I Palmero, Paul Mansfield, Lizet E van der Kolk, Annemieke Cats, Jolanda M van Dieren, Sergi Castellví-Bel, Bryson Katona, Rachid Karam, Paulo S Pereira, Patrick R Benusiglio, Carla Oliveira

BACKGROUND: Diffuse gastric cancer (DGC) is the most common manifestation in germline variant carriers, with one study estimating a 49-57% lifetime risk by age 80. Knowledge on -associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce.

OBJECTIVE: Explore 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 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 -knockout gastric cancer (GC) cells and -humanised , we assessed -associated loss-of-function mechanisms.

RESULTS: -truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline -truncating carriers lose αE-catenin. These transcripts are non-functional in , 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 -truncating variant carriers is fivefold and eightfold lower than in pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in -truncating and 38-fold higher in -truncating variant carriers. LBC is recurrent among -truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for genetic testing produced the 'Porto' criteria, which increased -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 -truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to downregulation. We demonstrate that compared with , is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for -carrier individuals and families.

© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

PMID: 40998418

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