Microsatellite instability (MSI) results from defects in the mismatch repair (MMR) system. In colorectal cancer, which gene is most frequently silenced by epigenetic promoter methylation (as opposed to germline mutation in Lynch syndrome) to cause sporadic MSI-high colorectal cancer?

• A MLH1 ✓
• B MSH2
• C MSH6
• D PMS2

Explanation

In sporadic MSI-high colorectal cancer (approximately 15% of all CRCs), MLH1 promoter hypermethylation is the dominant mechanism inactivating the mismatch repair system — causing MLH1 protein loss and microsatellite instability. This is frequently associated with BRAF V600E mutation and the serrated adenoma/CpG island methylator phenotype (CIMP) pathway. In Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC), germline mutations in MLH1, MSH2, MSH6, or PMS2 are causative, with MLH1 and MSH2 being most commonly mutated.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.