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Sporadic MSI-H Pattern — SCE Medical Oncology MCQ

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HardGI CancersSporadic MSI-H PatternSCE Medical Oncology

A 72-year-old with colorectal cancer and no suggestive family history has loss of MLH1 and PMS2. Tumour testing shows BRAF V600E and MLH1 promoter hypermethylation. Which molecular interpretation is most likely?

Educational content. Not a substitute for clinical judgement or local policy.

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Correct answer: A — Sporadic mismatch-repair deficiency caused by somatic MLH1 promoter methylation

Explanation lettering: D = shown as A · E = shown as C · A = shown as D · C = shown as E

D is correct. In a tumour with abnormal MLH1 expression, NICE uses BRAF V600E followed, when needed, by MLH1 promoter methylation to identify the common sporadic methylated pathway. The combination here strongly favours sporadic dMMR rather than Lynch syndrome. A is biologically unusual and ignores both sporadic markers. B would characteristically affect MSH2/MSH6. C assigns the wrong protein-loss pattern. E generally produces an ultramutated but mismatch-repair-proficient phenotype. “Sporadic” is the molecular interpretation, not an absolute prohibition on genetics review if age, pedigree, multiple tumours or unusual findings create residual concern.

Reference: NICE HTG430 molecular testing for Lynch syndrome: https://www.nice.org.uk/guidance/htg430/chapter/1-Recommendations