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

Background 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. Objective Explore CTNNA1 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 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. Results 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. Conclusion 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.