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What is Lynch syndrome?

Lynch syndrome is an inherited condition that greatly increases a person’s lifetime risk for developing colorectal cancer. Lynch syndrome also increases the risk for several other types of cancer, including endometrial cancer (uterine cancer), ovarian cancer, gastric (stomach) cancer and other, less common types of cancer. People with Lynch syndrome often develop colon cancer at an earlier age than people who develop sporadic colon cancer randomly.

It is the most common inherited form of colorectal cancer; 3-5% of all colorectal cancer patients are diagnosed with Lynch syndrome and about 1 in 300 people have a harmful genetic mutation in their DNA that causes Lynch syndrome.

The average age of onset of colon cancer in Lynch syndrome patients is between 40-60, while the average age in sporadic patients is between 67-71.

The genetic mutation for inherited cancer runs in families from one generation to the next, and parents can pass the mutation to their children. When one parent has Lynch syndrome, each child has a 50% chance of having Lynch syndrome.

If you or a family member has a history of cancer, you should talk to your doctor about inherited risk. There are tests available that identify the genes that indicate the presence of Lynch syndrome.

What causes Lynch syndrome?

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

Cells are the building blocks of our bodies. 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.

What are the risk factors for Lynch syndrome?

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 cancer diagnosis 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.

How is Lynch syndrome diagnosed?

Predicting Lynch Syndrome

Two screening tests can predict Lynch syndrome. Your doctor will take a sample of the tumor tissue (called 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.

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

When You Get A Positive Diagnosis

Here are some important things to know:

  1. Your diagnosis affects all of your immediate family members. They may have inherited the same mutation as you and 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.
  2. 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.

Lynch syndrome and cancer screening

People with Lynch syndrome should get screened early and often. Talk with your doctor about a screening plan to reduce your risk of developing colorectal or other cancers.

Early Screening Saves Lives

Start at the age of 20-25, or 2- 5 years younger than the youngest relative who was diagnosed with colorectal cancer.

Screen Often

Continue with colonoscopy every 1-2 years until the age of 40, even if no polyps or pre-cancerous growths are found. Make sure to get a colonoscopy every year after 40.

What To Do With Polyps

  1. If a polyp (adenoma) is found, it should be removed by endoscopy and continue with colonoscopy every 1-2 years.
  2. If a polyp cannot be removed by endoscopy, discuss with your doctor the surgical options best suited for you. Your doctor may suggest surgery to remove an extended portion of the colon or full colectomy (removal of the whole colon). Even after surgery, you should continue with colonoscopy to examine the remaining colon and rectum every 1-2 years.
  3. If an advanced polyp is found during your colonoscopy, discuss with your doctor the different surgical options most suited for you and continue to have a colonoscopy to examine the remaining colon and rectum every 1-2 years.
  4. It is common for people with Lynch syndrome to have flat polyps that can be difficult to detect. Talk to your doctor about new colonoscopy techniques that may improve the chance of catching those polyps.

Other Important Things to Know

Here are some other important considerations. Talk to your doctor about your options.

  • Plan for annual total body skin exams.
  • Studies show that daily aspirin may reduce the risk of developing colorectal cancer and other types of cancer in people with Lynch syndrome.
  • Some people with Lynch syndrome may consider surgically removing their whole colon (prophylactic colectomy), even before cancer is detected, to reduce the risk of developing colorectal cancer.

For Women:

  • Women with Lynch syndrome should have a screening plan for endometrial cancer and ovarian cancer that includes an annual transvaginal ultrasound beginning at age 30 and a blood test for the CA125 biomarker.
  • Consider having surgery to remove your uterus (hysterectomy) and ovaries (oophorectomy) to reduce risk of endometrial and ovarian cancers.

Treatment options for Lynch syndrome

Lynch syndrome patients with colon cancer are treated similarly to colon cancer patients without Lynch syndrome. The specific treatment will depend on the stage of diagnosis and the patient’s overall health.

  • Surgery: Surgery may be recommended to remove localized tumors. Due to the high risk of developing more tumors in the future, your doctor may recommend removing a large part of your colon or the whole colon.
  • Chemotherapy: 5FU-based therapies (FOLFOX, CAPOX) is the standard of care with the addition of oxaliplatin in metastatic cancer. The addition of targeted therapies depends on the sidedness of the tumor with anti-EGFR therapy for left-sided tumor and wildtype KRAS, and anti-VEGF therapy (bevacizumab) for right-sided tumors or those with KRAS mutations.
  • Immunotherapy: Because the majority of Lynch tumors are MSI-H, patients benefit from treatment with immune checkpoint inhibitors. Treatment with checkpoint inhibitors is currently a second-line of therapy, but there are ongoing clinical trials for immunotherapy as first-line therapy.

DOWNLOAD: Lynch Syndrome

Learn more about Lynch Syndrome.

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Family history overview

Learn about the role family history plays when it comes to colorectal cancer prevention and screening. 

What is FAP syndrome?

Learn more about familial adenomatous polyposis (FAP), an inherited disorder characterized by cancer of the colon and rectum.

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