## Molecular Pathogenesis of Lynch Syndrome–Associated Endometrial Carcinoma **Key Point:** Lynch syndrome (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, leading to microsatellite instability (MSI) and endometrial carcinoma as a major malignancy risk. ### Mismatch Repair Gene Mutations **Mnemonic:** **MLH1, MSH2, MSH6, PMS2** — the four main MMR genes mutated in Lynch syndrome. - **MLH1** (~60% of Lynch cases): Most common - **MSH2** (~25%): Second most common - **MSH6** (~10%): Associated with later-onset cancers - **PMS2** (~5%): Rare, milder phenotype ### Microsatellite Instability (MSI) 1. **Definition:** Expansion or contraction of repetitive DNA sequences (microsatellites) due to defective mismatch repair 2. **Detection:** PCR-based testing or immunohistochemistry for MLH1, MSH2, MSH6, PMS2 loss 3. **Consequence:** Accumulation of mutations in genes with microsatellite repeats → malignant transformation 4. **Frequency in Lynch-associated EC:** ~90% of endometrial carcinomas in Lynch syndrome show MSI-high ### Endometrial Cancer Risk in Lynch Syndrome - **Lifetime risk:** 40–60% (second most common malignancy after colorectal cancer) - **Histology:** Typically endometrioid adenocarcinoma - **Age of onset:** Often premenopausal (median ~50 years) - **Prognosis:** Better than sporadic high-grade endometrial cancer due to earlier detection and endometrioid histology **Clinical Pearl:** Screening for Lynch syndrome should be considered in all women with endometrial carcinoma diagnosed before age 50, or any endometrial cancer with MSI-high or loss of MMR protein on IHC. **High-Yield:** MSI is NOT the same as aneuploidy. Serous carcinomas (TP53-driven) are typically microsatellite-stable (MSS) and aneuploid, whereas Lynch-associated endometrial carcinomas are MSI-high but often diploid. [cite:Robbins 10e Ch 22]
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