What is Lynch Syndrome?
Lynch Syndrome, also called Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is an inherited syndrome of high colorectal cancer risk. Inherited or hereditary syndromes are health conditions that are passed from parents to children. Lynch Syndrome is caused by mutations in the DNA mismatch repair genes or genes that affect mismatch repair gene expression. These Lynch Syndrome genes include MLH1, MSH2, MSH3, MSH6, EPCAM, and PMS2. MLH1 and MSH2 mutations are the most common cause of Lynch Syndrome.
During organ and tissue growth, or healing of organ and tissue damage, your cells divide to make more cells. As each cell splits, the DNA divides and makes a copy of itself for the new cells. This is called DNA replication. Mistakes that occur in the copying process are called DNA mismatch. In patients with Lynch Syndrome, the ability to repair these common mistakes is impaired or deficient.
Lynch Syndrome causes 2-4% of colorectal cancers (bowel cancers). 60-80% of men with Lynch Syndrome and 40-60% of women with Lynch Syndrome will develop colon cancer or rectal cancer. And the level of risk varies by which MMR gene mutation is present. Lynch Syndrome is also associated with a high risk of other cancers, including endometrial cancer (uterine cancer), stomach (gastric) cancer, and ovarian cancer.
How is Lynch Syndrome tested?
When testing for Lynch Syndrome, your medical team is looking specifically at your genes, not your tumor’s genes. Initial laboratory testing on tumor (tumour) tissue, called immunohistochemistry (IHC), may be performed to screen for abnormalities in the mismatch repair (MMR) proteins. IHC is a method of testing proteins in a tissue biopsy by adding an antibody probe created in the laboratory that will attach to the proteins (antigens) of interest, in this case mismatch repair proteins. The antibody probe is also bound to a chemical compound that makes it visible under a microscope. This can be used to measure the amount of MMR proteins by looking at the amount of the visible antibody probe bound to it.
Genetic testing for Lynch-causing mutations in the MMR genes is performed on a blood sample or on cells collected from your mouth or saliva. Testing for Lynch Syndrome is often accompanied by consultation with a genetic counselor, a healthcare provider with cancer genetics training. Genetic counselors provide risk assessment, education, and support for patients and families that may be affected by a genetic syndrome.
What do my Lynch Syndrome testing results mean?
If you do not have Lynch Syndrome, your results will be reported as “negative” or “no pathogenic mutation detected”.
If you have Lynch Syndrome, your report will say “positive”, “pathogenic mutation detected”, or “variant detected, likely pathogenic” and will name the gene in which the mutation was found, like MLH1 or MSH2.
How do my Lynch Syndrome results impact my colorectal cancer treatment?
If you do not have a pathogenic mutation in one of your MMR genes
- You do not have Lynch Syndrome.
- Your prognosis will be determined from other information about your tumor, like the results of other biomarker testing and your cancer stage.
- Your treatment options include traditional chemotherapy, targeted therapy, and immunotherapy as indicated by the results of your other biomarker testing.
If you have a pathogenic mutation in one of your MMR genes
- You have Lynch Syndrome.
- Immunotherapy with immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy), is effective against Lynch Syndrome associated colorectal cancers.
- Immune checkpoint inhibitors use your own immune system to kill cancer cells by promoting stronger responses against cancer cells from white blood cells in your tumor (tumor-infiltrating lymphocytes).
- Fluorouracil-based adjuvant chemotherapy may be less effective in Lynch Syndrome associated stage II CRC. Adjuvant therapy is a secondary treatment given after the primary treatment to prevent recurrence of the cancer. Usually this is drug therapy that treats cancer cells that may remain in the body after surgery.
How does Lynch Syndrome affect my risk of other cancers?
If you have Lynch Syndrome, you have a higher risk of several different types of cancer including colorectal cancer, endometrial cancer (uterine), stomach cancer (gastric), ovarian cancer, pancreatic cancer, and prostate cancer. Lynch Syndrome is also associated, though less frequently, with cancer of the small intestine (small bowel), biliary tract cancer (gallbladder and bile ducts), urinary tract cancer (kidneys, ureters, and bladder), and some skin cancers. The level of risk depends on which mutation you have. For example, MLH1 and MSH2 mutations lead to a lifetime cancer risk of 70-80%, while MSH6 and PMS2 mutations are associated with a 25-60% lifetime risk of cancer.
You will need lifelong screening for Lynch Syndrome related cancers. Talk to your oncology team about the timing and frequency of cancer screening tests. Your healthcare team may recommend prophylactic procedures such as colectomy (removal of the colon), hysterectomy (removal of the uterus), or oophorectomy (removal of the ovaries) to lower your risk of cancer.
How does Lynch Syndrome affect my family members?
Because Lynch Syndrome is inherited, it is critical that your biological family members know about your diagnosis of Lynch Syndrome and have their own genetic testing. Family members who are diagnosed with Lynch Syndrome will start cancer screenings (such as colonoscopy) at a younger age than the general population and may be tested more frequently. If you have consulted with a genetic counselor in your Lynch Syndrome testing process, they can help you with information for your family members.
Who should be tested for Lynch Syndrome?
All colorectal cancer (bowel cancer) patients with microsatellite instability (MSI-High) should be tested for Lynch Syndrome. Colorectal cancer patients with a family history of colorectal or other Lynch Syndrome associated cancers should be tested.
Colorectal cancer patients diagnosed at less than 50 years old should undergo genetic counseling and evaluation for Lynch and other hereditary colorectal cancer syndromes.
All biological family members (siblings, children, cousins) of patients with Lynch Syndrome should themselves be tested. An early Lynch Syndrome diagnosis can prevent colorectal cancer in family members.