Which gene mutation is the most commonly associated with hereditary gastric cancer predisposition?

• A. PLAB2
• B. CDH1
• C. MSH2
• D. MLH1

Answer: (B)

Mutations in CDH1 are the primary genetic cause of hereditary gastric cancer predisposition. CDH1 encodes E-cadherin, a protein essential for maintaining cell–cell adhesion in the stomach lining. When this function is lost, cells detach and invade more easily, fostering diffuse-type gastric cancer that often appears at a younger age and runs in families. This pattern defines hereditary diffuse gastric cancer, making CDH1 the gene most strongly linked to hereditary gastric cancer risk.

The other genes are associated with different cancer syndromes. MSH2 and MLH1 are mismatch repair genes tied to Lynch syndrome, which raises colorectal and other cancer risks; gastric cancer can occur but is not the hallmark predisposition here. PALB2 is mainly linked to breast and pancreatic cancers, not a major contributor to hereditary gastric cancer.