A tumour shows microsatellite instability-high (MSI-H) status on PCR testing and loss of MLH1 expression on immunohistochemistry, but MLH1 gene sequencing shows no germline mutation. The most likely epigenetic mechanism responsible for this sporadic MSI-H colorectal cancer is:
- A Histone H3K27 acetylation of MLH1 enhancer
- B MLH1 promoter hypermethylation ✓
- C MLH1 mRNA alternative splicing due to ADAR editing
- D MLH1 protein ubiquitination and proteasomal degradation
Explanation
In approximately 80% of sporadic MSI-H colorectal cancers, the MLH1 mismatch repair gene is silenced by CpG island promoter hypermethylation rather than germline mutation (which would indicate Lynch syndrome). This epigenetic silencing prevents MLH1 transcription, resulting in absent MLH1 protein on IHC and downstream mismatch repair deficiency. Testing for BRAF V600E mutation alongside MLH1 methylation helps distinguish sporadic cases (BRAF mutated, MLH1 methylated) from Lynch syndrome (BRAF wild-type, no methylation, germline mutation). Histone acetylation would activate rather than silence gene expression.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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