Hereditary diffuse gastric cancer spectrum associated with germline <i>CTNNA1</i> loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls.

Abstract

Diffuse gastric cancer (DGC) is the most common manifestation in germline <i>CTNNA1</i> variant carriers, with one study estimating a 49-57% lifetime risk by age 80. Knowledge on <i>CTNNA1</i>-associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce. Explore <i>CTNNA1</i> 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 <i>CTNNA1-</i>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 <i>CTNNA1</i>-knockout gastric cancer (GC) cells and <i>CTNNA1</i>-humanised <i>Drosophila</i>, we assessed <i>CTNNA1</i>-associated loss-of-function mechanisms. <i>CTNNA1</i>-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline <i>CTNNA1</i>-truncating carriers lose αE-catenin. These transcripts are non-functional in <i>Drosophila</i>, 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 <i>CTNNA1</i>-truncating variant carriers is fivefold and eightfold lower than in <i>CDH1</i> pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in <i>CTNNA1</i>-truncating and 38-fold higher in <i>CDH1</i>-truncating variant carriers. LBC is recurrent among <i>CTNNA1</i>-truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for <i>CTNNA1</i> genetic testing produced the 'Porto' criteria, which increased <i>CTNNA1</i>-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 <i>CTNNA1</i>-truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to <i>CTNNA1</i> downregulation. We demonstrate that compared with <i>CDH1</i>, <i>CTNNA1</i> is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for <i>CTNNA1</i>-carrier individuals and families.