Introduction Germline CTNNA1 variants have emerged as an important cause of hereditary diffuse gastric cancer (HDGC), yet their clinical penetrance, disease spectrum and biological mechanisms have remained poorly defined. Unlike the classical HDGC gene CDH1, uncertainty surrounding CTNNA1-associated cancer risk has limited the development of evidence-based surveillance and prophylactic strategies.
Introduction
Germline CTNNA1 variants have emerged as an important cause of hereditary diffuse gastric cancer (HDGC), yet their clinical penetrance, disease spectrum and biological mechanisms have remained poorly defined. Unlike the classical HDGC gene CDH1, uncertainty surrounding CTNNA1-associated cancer risk has limited the development of evidence-based surveillance and prophylactic strategies. This large international study integrated molecular, functional and clinical data from 351 carrier families and more than 37,000 controls to clarify genotype–phenotype associations and refine clinical testing criteria.
Problem Statement
The study demonstrated that truncating CTNNA1 variants are the clinically relevant oncogenic alterations driving HDGC predisposition. CTNNA1 truncating transcripts underwent nonsense-mediated decay, resulting in loss of αE-catenin expression in diffuse gastric cancers. Carriers of truncating variants had an eightfold higher likelihood of diffuse gastric cancer compared with non-truncating carriers, while lobular breast cancer also recurred within affected families. Importantly, CTNNA1 behaved as a moderate-penetrance HDGC gene, with substantially lower gastric and breast cancer risk than CDH1. In contrast, non-truncating variants clustered within the αE-catenin middle fragment domain and were strongly associated with macular dystrophy patterned-2 rather than cancer predisposition.
Summary
This study substantially redefines the CTNNA1-associated HDGC spectrum and provides the strongest evidence to date supporting truncating CTNNA1 variants as pathogenic drivers of diffuse gastric cancer susceptibility. The authors propose simplified “Porto” testing criteria that improve identification of clinically relevant CTNNA1 carrier families while maintaining diagnostic specificity. The findings support individualized surveillance and prophylactic strategies distinct from those used in CDH1-associated HDGC, recognizing CTNNA1 as a moderate-risk gastric cancer predisposition gene rather than a highly penetrant syndrome. These data also establish a mechanistic framework for future CTNNA1 variant classification and precision hereditary gastric cancer management.
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