To determine the likelihood of Lynch syndrome, there are simple screening tests that can be performed on the tumor tissue of patients diagnosed with colon or endometrial cancer. The two most common screening tests are immunohistochemistry testing (IHC) and microsatellite instability testing (MSI). The results of these tests can be used to determine if more specific genetic testing should be considered.
Immunohistochemistry is a screening test for Lynch syndrome tumors that looks for the proteins expressed by the mismatch repair (MMR) genes. If the MMR genes are functioning properly, the proteins will be present. The absence of a mismatch repair protein increases the likelihood that the patient has Lynch syndrome and indicates that further genetic testing should be performed.
High microsatellite instability (MSI-H) in tumor tissue has come to be known as a trademark biomarker of Lynch syndrome. MSI-H status indicates that certain sections of DNA called microsatellites have become unstable and changed in length due to the major MMR genes that correct errors during DNA replication not functioning properly; the spell check is essentially missing on the DNA. A DNA analysis test is used to determine MSI status. The test is performed on both normal and tumor tissue. If the results for the tumor differ from the normal tissue results, the tumor is considered MSI-H. It’s important to note that not all tumors that are MSI-High are associated with Lynch syndrome, which is why further testing is needed for patients with MSI-H tumors.
Following confirmation that a patient is either missing one of the MMR proteins or is MSI-high, the next step is to test the MLH1 promoter for methylation, which is a common cause of MMR deficiency. If no methylation is detected, then the final step in the testing cascade is germline sequencing of the four MMR genes in order to determine whether the patient has a Lynch syndrome-associated mutation or if the MMR deficiency can be attributed to double somatic mutations. Around 4% of patients who complete this testing cascade will learn that they are positive for Lynch syndrome, meaning they inherited a MMR gene mutation from a parent. Following this diagnosis, genetic counselors will work with patients to help explain the significance of Lynch syndrome status and walk through next steps with them 2.