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

Question

Accepted Answer

A. CDH1. ## 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.**

Answer

B. TP53

Answer

C. MLH1

Answer

D. BRCA1

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)

CDH1 Gene and E-Cadherin Function

Clinical Management of CDH1 Carriers

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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