What is Lynch syndrome?

Lynch Syndrome: A Genetic Predisposition to Multiple Cancers

Lynch syndrome is an autosomal dominant genetic disorder caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletions in the EPCAM gene, which significantly increases the risk of colorectal cancer (up to 80%) and various other cancers including endometrial, ovarian, urinary tract, gastric, and pancreatic malignancies. 1

Genetic Basis and Pathophysiology

• Lynch syndrome results from mutations in MMR genes that normally function to repair DNA errors during cell replication, particularly in microsatellite regions 1
• These mutations lead to the accumulation of DNA errors in replicating cells, causing microsatellite instability (MSI) and increasing cancer risk 1
• The most commonly affected genes include:
  • MLH1, MSH2 (most common, with MSH2 mutations carrying higher risk for urinary tract cancers)
  • MSH6, PMS2 (generally associated with lower cancer risks)
  • EPCAM gene deletions (lead to MSH2 silencing) 1

Epidemiology and Prevalence

• Lynch syndrome affects approximately 1 in 440 Americans, making it one of the most common hereditary cancer syndromes 1
• It accounts for 2-4% of all colorectal cancers and 2-3% of endometrial cancers 1
• The majority of individuals with Lynch syndrome remain undiagnosed 1, 2

Cancer Risk Profile

• Colorectal cancer: 22-80% lifetime risk (varies by specific gene mutation) 1
• Endometrial cancer: 60% lifetime risk in women 1
• Other associated cancers include:
  • Upper tract urothelial carcinoma (2.9-28% lifetime risk)
  • Gastric and small intestinal cancers
  • Pancreatic cancer
  • Biliary tract cancer
  • Ovarian cancer
  • Brain tumors (usually glioblastoma)
  • Sebaceous gland tumors (Muir-Torre syndrome variant) 1

Clinical Presentation and Diagnosis

Diagnostic Criteria

• Historical criteria include:
  • Amsterdam II criteria: Family history of 3 relatives with Lynch syndrome-associated cancer, with one being a first-degree relative of the other two, at least 2 successive generations affected, and at least 1 cancer diagnosed before age 50 1
  • Revised Bethesda criteria: Less stringent guidelines including colorectal cancer diagnosed before age 50, synchronous or metachronous Lynch syndrome-associated tumors, or specific histological features 1

Identification of At-Risk Individuals

• Consider Lynch syndrome when:
  • Upper tract urothelial carcinoma presents before age 60 1
  • Patient meets the "3-2-1 rule": 3 affected relatives, across 2 generations, with 1 diagnosed before age 50 1
  • Colorectal cancer with microsatellite instability-high histology diagnosed before age 60 1
  • Family history of Lynch syndrome-associated cancers 1

Diagnostic Testing

• Risk assessment using prediction models based on personal and family cancer history 1
• Tumor tissue testing:
  • Immunohistochemistry (IHC) to detect loss of MMR protein expression
  • Microsatellite instability (MSI) testing 1
• Germline genetic testing to identify pathogenic variants in MMR genes 1

Cancer Surveillance and Prevention

• Colorectal cancer screening:
  • Colonoscopy every 1-2 years beginning in the 20s 1
  • This reduces colorectal cancer risk by 77% 1
• Upper tract urothelial carcinoma screening:
  • At minimum, routine urinalysis using ≥3 red blood cells per high power field as a trigger for further evaluation 1
• Other surveillance measures based on specific cancer risks 1
• Preventive strategies:
  • Daily aspirin may reduce cancer risk 1
  • Prophylactic gynecological surgery for women 2

Clinical Management Considerations

• Lynch syndrome colorectal cancers have distinct features:
  • Develop at younger ages than sporadic cases
  • More rapid adenoma-to-carcinoma progression (approximately 35 months vs. 10-15 years in sporadic cases)
  • Often poorly differentiated with lymphoid host response
  • Better stage-for-stage survival compared to sporadic colorectal cancer 1
• Upper tract urothelial carcinoma in Lynch syndrome:
  • Presents at younger age than sporadic cases
  • Higher proportion of ureteral (vs. renal pelvis) involvement
  • Female preponderance
  • Possible predisposition to bilateral disease 1

Genetic Counseling and Family Testing

• Genetic counseling is essential for:
  • Understanding inheritance patterns (autosomal dominant)
  • Risk assessment for family members
  • Reproductive decision-making 3
• Cascade testing of family members is recommended when a pathogenic variant is identified 2

Lynch syndrome represents a significant cancer predisposition that requires lifelong surveillance and preventive measures. Early identification through appropriate screening and genetic testing is crucial for reducing morbidity and mortality through targeted cancer prevention strategies.