A 32-year-old woman has an adenocarcinoma of the caecum. Immunohistochemistry shows loss of nuclear expression of MSH2 and MSH6, with intact MLH1 and PMS2. Germline testing should first target a mutation in which gene?

• A MLH1
• B MUTYH
• C PMS2
• D MSH2 ✓

Explanation

MSH6 functions as a heterodimer with MSH2, so loss of MSH6 alone can reflect an underlying MSH2 defect; paired loss of MSH2 and MSH6 points to a germline MSH2 mutation causing Lynch syndrome. Isolated MLH1 loss usually reflects BRAF-driven promoter hypermethylation in sporadic tumours, and PMS2 loss pairs with MLH1 defects. MUTYH-associated polyposis is recessive and typically shows multiple adenomas rather than isolated MSH2 loss.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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