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.
Gut (BMJ) published a clinical update in Research Highlights on 07 Apr 2026.
The item focuses on 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.
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