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
Menée à partir de données moléculaires, cliniques et démographiques provenant de 1 308 personnes issues de 351 familles porteuses d'un variant constitutionnel au niveau du gène CTNNA1 et provenant de 37 428 témoins d'ascendance européenne ou américaine, cette étude met en évidence une association entre la présence de variants entraînant une perte de fonction de CTNNA1 et le risque de cancer gastrique diffus ou de cancer lobulaire du sein puis identifie le mécanisme impliqué dans cette perte de fonction
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.
Gut , article en libre accès, 2025