Lynch syndrome

Lynch syndrome is caused by a harmful change (mutation) in one of five genes: MLH1, MSH2, MSH6, PMS2, or EPCAM.

When cells grow and divide, the genetic information (the DNA) in each cell has to be copied into the new cells without mistakes. The genes MLH1, MSH2, MSH6, and PMS2 work together as “spell checkers” to correct mistakes as they happen. This quality control process is called DNA Mismatch Repair (MMR).

Mutations in any one of the MMR genes “turn off” their spell checking activity and harm the quality control process. This results in errors in cells deficient in MMR (dMMR).

By chance, some of these uncorrected errors will be cancer-causing mutations, causing the cells to grow endlessly and create tumors.

The risk factors listed below (also called the revised Bethesda guidelines) will alert your doctor to consider genetic counseling and genetic testing for Lynch syndrome:

• Colorectal or endometrial cancerdiagnosis before the age of 50.
• Diagnosis of colorectal or any other cancer associated with Lynch syndrome.
• Colorectal cancer diagnosis and biomarker test results showing a tumor with high microsatellite instability (MSI-H).
• First-degree relative diagnosed with colorectal or endometrial cancer before the age of 50.
• Two or more first or second degree relatives diagnosed with colorectal or any other Lynch syndrome-associated cancer.

Two screening tests can predict Lynch syndrome. Your doctor will take a sample of the tumor tissue (a biopsy) to do one or two tests.

• Microsatellite Instability (MSI) Test: Microsatellites are short repetitive DNA sequences. This test compares these repetitive sequences from normal tissue against samples from cancer tissue. Significant differences in the number of sequences means there is microsatellite instability or positive MSI-H, common in more than 90% of Lynch syndrome tumors.

   

• Immunohistochemistry (IHC) Test: This test uses a special staining process to show the presence or absence of MMR proteins (MLH1, MSH2, MSH6, and PMS2) in cancer cells. Presence of all four proteins shows normal MMR function and little chance of Lynch syndrome (unless you have a strong family history or were diagnosed before the age of 50). A lack of staining suggests a lack of MMR proteins and is a sign of Lynch syndrome.

The genetic test used to diagnose Lynch Syndrome is done by collecting a blood or saliva sample and sending to a diagnostic lab for MMR gene mutation analysis.

Sometimes other genes will be tested for mutations too. Genetic counselors can help you understand the results and answer any questions.

• Positive results mean a mutation was found in one of the MMR genes.
• Negative results mean no mutation was found in any of the MMR genes.
• Uncertain results means that some variations (changes) were found in the DNA, but it is unclear whether those changes increase the risk of being diagnosed with cancer.

If you get a positive diagnosis, here are some important things to know:

• Your diagnosis affects all of your immediate family members. They may have inherited the same mutation as you and may have a higher risk of developing cancer.
• It is important that you tell your family members about your diagnosis so they can talk to their doctors.
• Your family members can be tested for Lynch syndrome even if they do not have cancer.
• If you are considering starting a family, talk with your doctor about your diagnosis of Lynch syndrome.
• There are many options to explore, including assisted reproductive technology and prenatal diagnosis.