Which gene mutation is associated with hereditary diffuse gastric cancer (HDGC) and is the primary target for prophylactic total gastrectomy?

Explanation

## Hereditary Diffuse Gastric Cancer (HDGC) **Key Point:** CDH1 (E-cadherin) gene mutations account for ~40–50% of hereditary diffuse gastric cancer cases and confer a lifetime risk of 70–80% for gastric cancer in carriers. ### CDH1 Gene and E-Cadherin Function 1. **Gene location:** Chromosome 16q22.1 2. **Protein product:** E-cadherin (a calcium-dependent cell adhesion molecule) 3. **Normal function:** Maintains cell–cell adhesion and acts as a tumor suppressor 4. **Loss of function:** Loss of E-cadherin leads to: - Reduced intercellular adhesion - Infiltrative growth pattern - Signet-ring cell formation - Early peritoneal and distant metastasis **High-Yield:** CDH1 mutations are inherited in an **autosomal dominant** pattern with **incomplete penetrance**. Carriers have a cumulative lifetime risk of 70–80% for diffuse gastric cancer, typically presenting in the 4th–5th decade. ### Clinical Management of CDH1 Carriers | Intervention | Indication | Rationale | |--------------|-----------|----------| | **Prophylactic total gastrectomy** | Confirmed CDH1 mutation carriers | Eliminates risk; typically performed between ages 20–40 | | **Endoscopic surveillance** | Uncertain penetrance or family preference | High-definition endoscopy + chromoendoscopy; limited sensitivity | | **Genetic counseling** | Family members of carriers | Identify at-risk relatives | **Clinical Pearl:** Even with surveillance, early detection of diffuse gastric cancer is difficult because signet-ring cells are scattered throughout the mucosa and do not form a discrete lesion. **Mnemonic:** **CDH1 = Cadherin Defect = Hereditary Diffuse (not intestinal) gastric cancer.**