CpG island hypermethylation of promoter regions is a common epigenetic mechanism in cancer. When the MLH1 promoter is hypermethylated in sporadic colorectal cancer, the result is:

• A Silencing of MLH1 expression causing mismatch repair deficiency and MSI ✓
• B Overexpression of MLH1 with constitutive MMR activity
• C Amplification of the MLH1 gene causing excessive DNA repair
• D Alternative splicing generating a dominant-negative MLH1 protein

Explanation

CpG island methylation of the MLH1 promoter is the most common mechanism of MLH1 silencing in sporadic (non-hereditary) MSI-H colorectal cancers, accounting for ~15% of all CRC. Methylation-induced transcriptional silencing of this MMR gene creates a mismatch repair deficiency identical phenotypically to Lynch syndrome but epigenetically rather than genetically caused. This is distinguished from Lynch syndrome by somatic (rather than germline) methylation and is often associated with BRAF V600E mutation.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.