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

Abstract

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.

Keywords: ADHESION MOLECULES; CANCER GENETICS; GASTRIC CANCER; HEREDITARY CANCER SYNDROMES; MODELS, ANIMALS.