What is the most common germline mutation found in detected gastric cancers?

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

Answer: (D)

Mutations in CDH1 are the most common inherited defects linked to gastric cancer, specifically causing hereditary diffuse gastric cancer. CDH1 encodes E-cadherin, a protein essential for cell-cell adhesion; when this gene is inactivated, cells lose cohesion and tend to infiltrate the stomach wall diffusely, leading to the diffuse type of gastric cancer that often presents at a younger age. Because HDGC is the best-characterized germline gastric cancer syndrome, CDH1 mutations are the most frequently identified germline alteration in gastric cancer cases. In contrast, MSH2 and MLH1 are associated with Lynch syndrome and raise gastric cancer risk as part of a broader cancer spectrum, but they are not the most common germline mutations found in detected gastric cancers. PLAB2 isn’t a recognized major gastric cancer predisposition gene.