Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular comprehensive analysis

CTNNA1 (germline LOF, new HDGC gene)

Germline loss of function of CTNNA1 (α-catenin 1, adherens junction protein) → destabilization of membrane E-cadherin → HDGC phenotype similar to pathogenic CDH1 variants; lifetime risk estimated at 49–57% for diffuse gastric cancer

Complete clinical and molecular study of the HDGC spectrum associated with germline LOF variants of CTNNA1 (α-catenin 1). CTNNA1 interacts directly with E-cadherin (CDH1) and its loss of function results in an analogous HDGC phenotype. The estimated lifetime risk for diffuse gastric cancer in CTNNA1 carriers is 49–57% by age 80. This study consolidates the role of CTNNA1 as the second major HDGC predisposition gene, with direct management implications (prophylactic gastrectomy, endoscopic surveillance).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

CTNNA1 should be systematically included in hereditary diffuse gastric cancer predisposition panels, alongside CDH1. CTNNA1 LOF carriers should receive rigorous endoscopic surveillance and a discussion on prophylactic gastrectomy according to IGCLC criteria. Immediate impact for oncogeneticists managing CDH1-negative HDGC families.

new CDH1-like HDGC gene +3; high lifetime risk (49-57%) +2; Gut (top gastro journal) +2; direct clinical impact (endoscopic surveillance and prophylaxis) +1