Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is diagnosed by Amsterdam II criteria. Which molecular mechanism underlies Lynch syndrome?

• A Germline APC mutation causing accumulation of beta-catenin
• B Somatic KRAS mutation driving adenoma-carcinoma sequence
• C Germline mutation in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) causing microsatellite instability ✓
• D Biallelic MUTYH mutation causing base-excision repair deficiency

Explanation

Lynch syndrome results from germline loss-of-function mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 and MSH2, followed by MSH6 and PMS2. Defective MMR leads to microsatellite instability (MSI-high), detectable by PCR or immunohistochemistry. This carries implications for surveillance, surgical management (subtotal colectomy preferred over segmental) and systemic therapy (MSI-high tumours respond to PD-1 immune checkpoint inhibitors). MUTYH-associated polyposis is a distinct autosomal recessive condition. APC mutations characterise FAP.

Reference: Bailey & Love's Short Practice of Surgery, 27th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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