Lynch syndrome is an inherited genetic condition that significantly elevates an individual’s lifetime risk for several cancers, most notably colorectal and endometrial cancers. This predisposition stems from changes in specific genes involved in DNA repair. Identifying Lynch syndrome early through comprehensive testing is important for managing cancer risk and implementing tailored screening and prevention strategies.
Who Should Consider Testing
Considering testing for Lynch syndrome often begins with an evaluation of personal and family medical histories. Individuals with a strong family history of certain cancers, particularly colorectal, endometrial, ovarian, gastric, urinary tract, and pancreatic cancers, should explore testing options. The age at which family members were diagnosed with these cancers also plays a role, with earlier diagnoses raising greater suspicion. For instance, a diagnosis of colorectal cancer before age 50 in a close relative is a significant indicator.
Healthcare professionals use established guidelines to identify patterns in cancer diagnoses that suggest an inherited predisposition. Individuals who have had certain cancers themselves, especially if diagnosed at a younger age or if they have developed multiple primary cancers, should also discuss testing with their doctor.
Initial Screening Approaches
Initial screening for Lynch syndrome typically involves testing tumor tissue from individuals diagnosed with a Lynch-associated cancer. This process aims to identify characteristics in the cancer cells that suggest a problem with DNA mismatch repair, a hallmark of Lynch syndrome. Two primary methods are used for this initial assessment: immunohistochemistry (IHC) and microsatellite instability (MSI) testing.
Immunohistochemistry (IHC) assesses the presence or absence of specific proteins, namely MLH1, MSH2, MSH6, and PMS2, which are involved in the DNA mismatch repair process. In Lynch syndrome, a genetic change can lead to the absence or dysfunction of one or more of these proteins in tumor cells. A loss of expression for any of these proteins indicates a potential underlying mismatch repair deficiency, suggesting the possibility of Lynch syndrome.
Microsatellite instability (MSI) testing, the other common initial screening method, examines specific repetitive DNA sequences called microsatellites. In individuals with Lynch syndrome, errors in DNA replication often go uncorrected due to faulty mismatch repair genes, leading to changes in the length of these microsatellites within tumor cells. A high level of instability (MSI-H) in tumor tissue suggests a defective mismatch repair system, which is frequently observed in Lynch syndrome-associated cancers. While both IHC and MSI testing are valuable screening tools, their results indicate a likelihood of Lynch syndrome rather than a definitive diagnosis, as some individuals may develop these changes only in their cancer cells.
Genetic Testing for Lynch Syndrome
Genetic testing provides a definitive diagnosis of Lynch syndrome by looking for specific inherited changes in DNA. This testing is typically performed on a blood sample, though a saliva sample can also be used. The tests analyze the mismatch repair genes, specifically MLH1, MSH2, MSH6, and PMS2, and sometimes the EPCAM gene, which are known to be associated with Lynch syndrome.
The process involves extracting DNA from the collected sample and analyzing these specific genes for pathogenic variants, often referred to as mutations. A positive result signifies the identification of such a variant, confirming a diagnosis of Lynch syndrome.
Genetic counseling plays a significant role both before and after genetic testing. Prior to testing, a genetic counselor discusses the testing process, potential results, and their implications for the individual and their family. Following the test, counselors help interpret the results, explain the associated cancer risks, and outline recommended surveillance and risk management strategies.
Understanding Test Results
Interpreting Lynch syndrome test results involves understanding the different possible outcomes. A “positive” result means a pathogenic variant, or mutation, has been identified in one of the Lynch syndrome-associated genes. While a positive result does not guarantee cancer development, it prompts increased cancer surveillance and tailored risk management strategies.
Conversely, a “negative” result indicates that no pathogenic variant was found in the genes tested. This significantly reduces the likelihood of having Lynch syndrome. However, a negative result does not completely eliminate all cancer risk, especially if there is a strong family history of cancer, as other genetic or non-genetic factors may still contribute to risk.
Sometimes, genetic testing yields a “variant of uncertain significance” (VUS). This means a genetic change was found, but its clinical impact on cancer risk is not yet clear. VUS results are common in genetic testing and typically do not lead to immediate changes in medical management, requiring careful interpretation by healthcare professionals.