A 28-year-old Indian woman presents for genetic counseling. Her father died of diffuse gastric cancer at age 52, and her paternal grandmother had lobular breast carcinoma at age 65. Genetic testing reveals a germline mutation in the structure marked **A** in the diagram. Which of the following best explains why endoscopic surveillance with random biopsies is considered inadequate for this patient despite annual screening?

Question

Accepted Answer

D. Loss of E-cadherin-mediated cell adhesion produces discohesive signet-ring cells that infiltrate diffusely without forming a mass lesion, making endoscopic detection difficult with sensitivity ~60%. ## Why option 1 is correct

The structure marked **A** (CDH1 deletion 16q22.1) encodes E-cadherin, a calcium-dependent cell adhesion molecule. Loss of E-cadherin function results in discohesive signet-ring cells that infiltrate the gastric wall diffusely without forming a discrete mass lesion (linitis plastica pattern). This diffuse infiltration makes endoscopic detection notoriously difficult; even the Cambridge protocol (30 random biopsies from 6 gastric regions) achieves only ~60% sensitivity. This is precisely why the International Gastric Cancer Linkage Consortium (IGCLC) 2020 guidelines recommend prophylactic total gastrectomy between ages 20–30 for CDH1 mutation carriers, rather than relying on surveillance alone. The patient's family history (father with diffuse gastric cancer <55 years, paternal grandmother with lobular breast carcinoma) meets IGCLC criteria for CDH1 testing and confirms the need for definitive surgical management.

## Why each distractor is wrong

- **Option 2 (APC)**: APC mutations cause familial adenomatous polyposis (FAP) with multiple adenomatous polyps that are visible and detectable on endoscopy. This does not explain the difficulty in detecting diffuse gastric cancer caused by CDH1 mutations.
- **Option 3 (BRCA1)**: BRCA1 mutations predispose to breast and ovarian cancers primarily, not diffuse gastric cancer. While BRCA1 is involved in DNA repair, it is not the genetic basis for hereditary diffuse gastric cancer.
- **Option 4 (MLH1)**: MLH1 mutations cause Lynch syndrome (hereditary nonpolyposis colorectal cancer) with microsatellite instability. Although Lynch syndrome increases gastric cancer risk, it does not produce the characteristic signet-ring cell morphology or linitis plastica pattern seen with CDH1 mutations.

**High-Yield:** CDH1 mutations → loss of E-cadherin → discohesive signet-ring cells → diffuse infiltration without mass → poor endoscopic detection → prophylactic gastrectomy is definitive management.

[cite: Sabiston Textbook of Surgery 21e; IGCLC 2020 Guidelines]

Answer

A. APC mutations cause adenomatous polyposis with multiple polyps that are easily missed on standard endoscopy

Answer

B. BRCA1 mutations predispose to diffuse gastric cancer through impaired DNA repair mechanisms that are undetectable endoscopically

Answer

C. MLH1 mutations cause microsatellite instability leading to multiple synchronous gastric cancers that cannot be identified by biopsy alone

Explanation

Why option 1 is correct

Why each distractor is wrong

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