CDH1 (E-cadherin) promoter methylation resulting in gene silencing is the initiating molecular event in which hereditary cancer syndrome?

• A Lynch syndrome via MSH2/MLH1 mismatch repair loss
• B Hereditary diffuse gastric cancer (HDGC) syndrome with germline CDH1 mutation ✓
• C Familial adenomatous polyposis via APC truncation
• D Von Hippel-Lindau syndrome via VHL loss

Explanation

Hereditary diffuse gastric cancer (HDGC) is caused by germline CDH1 (E-cadherin) mutations; the second hit is typically promoter methylation of the remaining allele, silencing E-cadherin expression. Loss of E-cadherin disrupts the E-cadherin/beta-catenin complex, leading to decreased cell-cell adhesion and enabling the poorly cohesive (signet ring cell/diffuse-type) carcinoma morphology. This is distinct from MSI-driven gastric cancer (Lynch syndrome), APC-driven tubular adenoma-carcinoma sequence (FAP), or VHL loss leading to clear cell renal carcinoma — none of which involve CDH1 as the primary driver.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.