Definition
Lynch syndrome (also called hereditary nonpolyposis colorectal cancer, HNPCC) is an autosomal dominant inherited cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes.
- Leads to microsatellite instability (MSI-H) in tumors.
- Predisposes to colorectal, endometrial, and other cancers.
Genetics
- MMR genes involved: MLH1, MSH2, MSH6, PMS2
- EpCAM deletions → secondary MSH2 silencing
- Autosomal dominant inheritance → 50% risk for offspring
Associated Cancers
Clinical Features
- Early-onset cancers (often <50 years old)
- Family history: multiple relatives with Lynch-associated cancers
- Tumor characteristics: MSI-H, dMMR
Diagnosis
- Clinical criteria: Amsterdam II, revised Bethesda guidelines
- Genetic testing: Germline testing for MMR gene mutations
- Tumor testing: MSI testing or immunohistochemistry (IHC) for MMR protein loss
Management / Surveillance
Surveillance
- Colonoscopy: every 1–2 years starting at age 20–25
- Endometrial/ovarian screening: transvaginal ultrasound, endometrial biopsy
- Gastric/urinary tract surveillance: individualized
Surgical Prevention
- Prophylactic hysterectomy and bilateral salpingo-oophorectomy in women who have completed childbearing
Chemotherapy / Targeted Therapy
- Immunotherapy (PD-1 inhibitors, e.g., pembrolizumab) for MSI-H/dMMR tumors
- Standard chemotherapy per tumor type; response may vary depending on MSI status
Pharmacy / Clinical Considerations
- Immunotherapy dosing: Pembrolizumab 200 mg IV q3w or 400 mg q6w
- Monitor for immune-related adverse events (irAEs)
- Genetic counseling is essential for patients and family members
Prognosis
- Early detection and surveillance improve survival.
- MSI-H tumors (from Lynch syndrome) often respond well to checkpoint inhibitors.