[Lynch Syndrome -  the Pathologist's Diagnosis].

Area of Science:

• Genetics and Oncology
• Molecular Biology
• Cancer Research

Context:

• Lynch syndrome, the most common hereditary colorectal cancer, accounts for up to 5% of all colorectal cancers.
• It stems from germline mutations in DNA mismatch repair (MMR) genes, leading to microsatellite instability (MSI).
• Accurate diagnosis is crucial due to familial occurrence, lack of premorbid phenotype, and cancer development at reproductive age.

Purpose:

• To highlight the limitations of current clinical diagnostic guidelines for Lynch syndrome.
• To emphasize the superior sensitivity of modern pathology methods in detecting MSI.
• To outline the diagnostic workup for suspected Lynch syndrome.

Summary:

• Germline mutations in MMR genes cause Lynch syndrome, characterized by MSI and increased cancer risk, primarily colorectal cancer.
• Clinical diagnostic tools like the revised Bethesda guidelines lack sufficient sensitivity.
• Pathological diagnostics, including MSI detection, MMR protein analysis, BRAF gene testing, and MLH1 promoter methylation analysis, are more effective.
• Confirmation requires detecting MMR gene mutations in peripheral blood leukocytes.

Impact:

• Improved diagnostic accuracy for Lynch syndrome.
• Earlier identification of individuals at high risk for hereditary colorectal cancer.
• Facilitation of timely genetic counseling and personalized cancer management strategies.