From the Guidelines
To help rule out Lynch syndrome, initial diagnostic labs should include microsatellite instability (MSI) testing and immunohistochemistry (IHC) on tumor tissue to assess for deficient mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) as recommended by the American Gastroenterological Association institute guideline on the diagnosis and management of Lynch syndrome 1.
Key Diagnostic Labs
- Microsatellite instability (MSI) testing
- Immunohistochemistry (IHC) on tumor tissue to assess for deficient mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2)
Additional Testing
If abnormalities are found, genetic testing for germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) should be performed as suggested by the NCCN clinical practice guidelines in oncology 1.
Special Considerations
For patients with loss of MLH1 protein expression on IHC, BRAF V600E mutation testing and MLH1 promoter methylation analysis can help distinguish sporadic cancers from Lynch syndrome 1.
Next-Generation Sequencing
Next-generation sequencing panels that include Lynch syndrome-associated genes may be ordered to aid in the diagnosis of Lynch syndrome 1.
Importance of Early Identification
Early identification of Lynch syndrome allows for enhanced cancer surveillance and preventive measures for patients and their family members, which can significantly improve morbidity, mortality, and quality of life outcomes 1.
From the Research
Diagnostic Labs for Lynch Syndrome
To help rule out Lynch syndrome, the following diagnostic labs can be ordered:
- Microsatellite instability (MSI) testing 2, 3, 4, 5
- Mismatch repair protein immunochemistry 2, 3, 4
- Immunohistochemical investigation of MMR protein expression 4
- Molecular genetic investigation of the BRAF gene 4
- Methylation analysis of the MLH1 promoter 4
- Germline genetic testing for mutations in LS-associated mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM) 6, 5
- Next-generation sequencing methods to detect germline variants in mismatch repair genes 2
Rationale for Diagnostic Labs
These diagnostic labs are used to detect the presence of Lynch syndrome, which is characterized by a germline mutation in one of the mismatch repair genes. MSI testing and mismatch repair protein immunochemistry can identify tumors with high-frequency MSI, which is associated with Lynch syndrome 5. Germline genetic testing can confirm the presence of a mutation in a mismatch repair gene, which is essential for diagnosing Lynch syndrome 6, 5.
Importance of Diagnostic Labs
Accurate diagnosis of Lynch syndrome is crucial for identifying individuals at high risk of developing colorectal, endometrial, and other associated cancers. Early detection and prevention strategies, such as surveillance, prophylactic surgery, and chemoprevention, can improve clinical outcomes for individuals with Lynch syndrome 2, 6.