How do EPCAM deletions relate to Lynch syndrome mechanism?

• A. EPCAM deletions can lead to MSH2 silencing and MMR deficiency, contributing to Lynch syndrome risk
• B. EPCAM mutations cause BRCA-related cancers
• C. EPCAM has no role in Lynch syndrome
• D. EPCAM deletions cause FAP

Answer: (A)

EPCAM deletions contribute to Lynch syndrome risk by silencing the adjacent MSH2 gene, causing mismatch repair deficiency. EPCAM lies next to MSH2 on the chromosome, and deletions at the end of EPCAM can remove its transcriptional stop signal, allowing read-through into the MSH2 promoter. This triggers epigenetic inactivation (promoter methylation) of MSH2 in tissues where EPCAM is expressed, so MSH2 protein is not produced. Without functional MSH2, the DNA mismatch repair system fails to correct replication errors, leading to microsatellite instability and the cancer risk seen in Lynch syndrome. This mechanism shows that EPCAM deletions contribute to Lynch syndrome not by mutating MSH2 directly, but by causing its silencing. The other options don’t fit because BRCA-related cancers are tied to BRCA genes, not EPCAM; EPCAM does have a role in Lynch syndrome; and FAP is driven by APC, not EPCAM.