Lobo, S., Dias, A., Pedro, A.M., Ferreira, M., Pinto-Oliveira, A., São José, C., Herrera-Mullar, J., Pinto, N., Colas, C., Hüneburg, R., Nattermann, J., Boussemart, L., van Hest, L.P., Moreira, L., Horton, C., Farengo Clark, D., Tinschert, S., Golmard, L., Spier, I., López-Fernández, A., Oliveira, D., Svrcek, M., Bourgoin, P., Coulet, F., Delhomelle, H., Davis, J., Zäncker, B., Lazaro, C., Guerra, J., Almeida, M.L., Carrera, S., Patiño, A., Gundlach, P., Laszkowska, M., Strong, V.E., Teixeira, M.R., Schrader, I., Steinke-Lange, V., Gullo, I., Sousa, S., Batista, M., Aretz, S., Balmaña, J., Aronson, M., Antoniazzi, A.P., Palmero, E.I., Mansfield, P., van der Kolk, L.E., Cats, A., van Dieren, J.M., Castellví-Bel, S., Katona, B., Karam, R., Pereira, P.S., Benusiglio, P.R., Oliveira, C. (2026). 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.  Gut 75(5): 872--885.

FBrf0265065

Research paper

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. Explore CTNNA1 genotype-phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers. 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. 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. 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.

PMC13151538 (PMC) (EuropePMC)