Lynch Syndrome

Lynch syndrome is the most common form of hereditary colorectal cancer affecting more than 1.2 million people (about the population of New Hampshire) in the United States. Patients with Lynch carry an increased risk for certain cancers, such as colorectal, endometrial, ovarian, stomach, and more.

Early-age onset colorectal cancer is a flag for Lynch syndrome, and young patients should be tested.

Unfortunately, an estimated 95% of Lynch syndrome cases are undiagnosed.

Lynch syndrome genes

The Lynch syndrome genes are in a class of genes called mismatch repair (MMR). MMR genes work like “spell checkers.” Every time your body needs to make a new cell (which happens frequently), it makes an exact copy of your genetic material. The MMR genes “spell check” the new copy of DNA to identify any mistakes that were made while it was being copied, and then the genes repair those mistakes.

If the MMR genes are mutated and not working properly, these mistakes cannot be repaired, and the new cells will have an abnormal copy of its genetic material. This is known as MMR-deficient, or MMR-D.

When any one cell accumulates enough mistakes in its genetic material, it may start to grow out of control and not die when it should. That cell can become a cancer. There are four “repair” genes, or MMR genes, that can currently be tested for Lynch syndrome, and one gene is known to indirectly cause it:

• MLH1
• MLH2
• MSH6
• PMS2
• EPCAM (formerly TACSTD1) can “turn off” the MSH2 gene, therefore leading to this cancer syndrome.

Muir-Torre syndrome is an older term used to describe families with Lynch syndrome who have certain types of Lynch syndrome-related skin growths and cancers.

Turcot syndrome is an older term used to describe families with Lynch syndrome who have brain tumors (usually glioblastomas).

It is now known that anyone with Lynch syndrome can develop these skin growths/cancers and brain tumors so these names are not being used anymore.

How common is Lynch?

According to Cancer.Net, “Estimates suggest as many as 1 in every 300 people may be carriers of a change, also called an alteration or mutation, in a gene associated with Lynch syndrome.”

Approximately 3% of all colorectal cancer cases are the result of Lynch syndrome.

How will I know if I have it?

How and when you get tested for Lynch syndrome will depend on if you have or have not been diagnosed with cancer.

If you’ve had cancer

Many institutions now perform a screening test on all colorectal cancers and endometrial (uterine) tumors at the time of surgery. If you’re not sure if this test was done, ask your oncologist. If your surgery was not too long ago, it’s likely the test can still be performed if it wasn’t done.

Most hospitals do one of these two screening tests, if not both:

MICROSATELLITE INSTABILITY (MSI)

An MSI screening test looks for changes in the DNA sequence by comparing normal tissue and tumor tissue. Defects in the MMR genes (MMR-D) result in an increased accumulation of DNA errors, and stretches of DNA called microsatellites are especially prone to these errors.

Most cancers do not have errors in their microsatellites, this is known as a MSS or microsatellite stable tumor.

77-89% of Lynch-related tumors show MSI (also called MSI-high), but 10-15% of sporadic tumors also show it.

Given that both Lynch and sporadic tumors can show MSI, additional testing is needed to determine if an individual with an MSI-high tumor has Lynch syndrome.

Learn more about MSI vs MSS tumors.

IMMUNOHISTOCHEMISTRY (IHC)

An immunohistochemistry (IHC) test looks for missing proteins in tumor cells. The premise behind the test is that if the MMR genes are working properly, their protein products should be present in the tumor. However, if there is a mutation in one of the Lynch syndrome MMR genes, that gene’s protein will be absent in the tumor.

83-90% of Lynch-related tumors and 20% of sporadic tumors have at least one of these proteins absent.

IHC testing looks to see if a tumor is missing any of the MMR proteins. If any of the MMR proteins are missing, the test is abnormal, and you are more likely to have Lynch syndrome. This would need to be determined by doing genetic testing for Lynch syndrome genes. If the test is normal, you are less likely to have Lynch syndrome, but it cannot be ruled out entirely.

If you’ve not had cancer

If you have not been diagnosed with cancer, ask your biological family members who have cancer about their genetic testing results. This may influence your next steps. It’s important to work with a genetic counselor who can help you understand the process.
Your biological family history may give you clues that Lynch syndrome runs in your family and you would benefit from getting tested:

• There are multiple generations on one side of the family (great-grandparent, grandparent, parent, aunt/uncle, child) with a Lynch-associated cancer
• There may be “clustering” of Lynch-associated cancers in the family
• Individuals in the family may have more than one cancer
• Individuals may be diagnosed with cancer at younger ages than average

Many insurance plans and some genetic test providers will offer genetic testing if there’s been a diagnosis of Lynch syndrome in the family. It’s important to speak with a genetic counselor about your testing options.

To find a genetic counselor knowledgeable about hereditary gastrointestinal cancer, search the CGA-IGC map.

I am interested in genetic testing: What should I know?

Genetic testing can be beneficial for both the cancer patients and their biological family members. Patients should have their tumors tested following surgery, however, a follow-up with a genetic counselor is advised for both the patient and any family members. These follow-up visits often collect blood or saliva and use these samples for genetic testing.

Genetic test results

Typically, your results will come back:

• Positive/Clinically significant: you have a genetic mutation
• Variant of uncertain (or unknown) significance (VUS): there’s a variation in your gene, but it’s unknown if it leads to increased cancer risk
• Negative/No known mutation: there were no mutations found in the genes tested

Can my genetic test results change?

While your DNA findings should not change over time, testing does improve and mutations that were not identified previously can be identified. New genes may be discovered for which you were not originally tested. In addition, sometimes the meaning of your original test results will be reclassified. This means that new information has come in about your genetic mutation.

Most often, reclassification occurs when someone has previously tested VUS and the new result is negative (this is not clinically actionable).

More rarely, a VUS or negative result will be reclassified as positive or a positive result will be reclassified as negative or VUS (these changes are clinically actionable). Your genetic counselor will contact you if your test result has a clinically actionable reclassification.

Should I repeat my genetic testing?

Talk with your genetic counselor to form a game plan for your unique case and make sure you understand which genes are being tested. In some cases, depending on your health and your family member’s health, you may be tested for one gene, or a handful of genes. In other cases, a full panel may be run.

A genetic counselor can advise what type of testing you need, and how frequently.

In general, people tested prior to 2013 may need updated testing since that is when panel testing first became available (testing for multiple genes at one time).

Should I Use 23andMe for Lynch syndrome testing?

Although 23andMe has brought some awareness to hereditary colorectal cancer, it does not offer any tests that look at the Lynch syndrome genes. The 23andMe test looks at two common mutations in the MUYTH gene (not the entire gene), which is associated with a recessive condition (this means you have to have two mutations, one from each parent, to be affected) that causes colorectal polyps and cancer.

Currently 23andMe, along with other direct consumer testing options, could give a person a false sense of their overall colorectal cancer risk due to hereditary colorectal polyps/cancer genes. For more information, read our blog about using 23andMe’s test for colorectal cancer risk.

Genetic testing cost

Costs of genetic testing can vary depending on several factors including insurance plan, personal cancer history, family health history, and the genetic test provider. In most cases, the worst case scenario would be an out of pocket cost of ~$250.

Many laboratories offer financial assistance programs with no cost genetic test for those who earn less than 3-4 times the federal poverty limit.

Need financial help? The Mayberry Memorial’s Project Conquer offers grants to individuals who need genetic testing and genetic counseling.

Can you have Lynch syndrome if you don’t have a family history?

Although it’s uncommon, it is possible to carry a Lynch syndrome gene mutation and not have a family history. In these cases, the patient with Lynch is considered “de novo,” or the first in the family line to carry the mutation.

Lynch-associated cancers

If you have Lynch syndrome, your risk of several cancers is higher compared to others without the same mutated gene. There are several Lynch syndrome-associated cancers. Your risk for each cancer type will depend on your mutated gene, as well as if you’re biologically male or female.

Colon and rectal cancers

Up to 3-5% of all colorectal cancer is due to Lynch syndrome. People with Lynch syndrome have a 10-60% lifetime risk of developing colorectal cancer (compared to a 4% risk for people with average risk).

The average age of a colorectal cancer diagnosis for someone with Lynch syndrome can occur decades below the screening age of 45. Lynch syndrome is a common cause of colorectal cancer in young adults.

Colorectal cancer in Lynch syndrome patients may form quicker than in average-risk patients, and colorectal cancer screening, most often colonoscopy, will need to occur much more frequently for Lynch patients.

Endometrial (uterine) cancer

Women with Lynch syndrome carry an elevated risk of developing endometrial cancer. Depending on the mutated gene, there is a 15-60% lifetime risk. To prevent uterine cancer, doctors may recommend a prophylactic (preventive) hysterectomy if there are no plans for childbearing or if a woman is past the age for childbearing.

Ovarian cancer

Women with Lynch syndrome carry a 1-40% chance of developing ovarian cancer. To prevent ovarian cancer, doctors may recommend a prophylactic (preventive) oophorectomy (ovary removal) if there are no plans for childbearing or if a woman is past the age for childbearing.

Stomach cancer

Men and women with Lynch syndrome carry a 1-9% lifetime risk of developing stomach cancer.

Breast and prostate cancers

There are differing opinions on whether breast cancers and prostate cancers are part of Lynch-associated cancers. However, studies show that Lynch patients may carry an elevated risk for these cancers.

While half of breast cancer cases in women with Lynch appear to be caused by Lynch syndrome (they have abnormal IHC or are MSI-high), there is insufficient data supporting an increased risk for breast cancer among women with Lynch syndrome.

Men with Lynch carry an elevated risk for prostate cancer (as high as 24% for Lynch patients, particularly those with mutations in the MSH2 gene, compared to 13% for average-risk men).

Other related cancers

Lynch syndrome patients face an increased risk for several cancers compared to an average-risk person without a hereditary cancer syndrome. If any of the Lynch-associated cancers run in your family, it’s important to let your geneticist know.

• Upper urinary tract or renal pelvis cancer (up to 28%)
• Skin cancer (up to 9%)
• Pancreatic cancer (up to 6%)
• Small intestine cancer (up to 11%)
• Bladder (up to 13%)
• Hepatobiliary tract cancer (up to 4%)
• Brain/central nervous system cancer (up to 3%)

What should my family members do if I have Lynch syndrome?

Your biological, immediate family members (mother, father, adult siblings and children) should be tested for Lynch syndrome if you are positive. Most people diagnosed with Lynch syndrome inherited the mutation from one of their parents, and each of their children carry a 50% chance of also inheriting the mutation.

Does everyone with Lynch syndrome get cancer?

The diagnosis of a genetic syndrome can be scary, but knowledge is power! The sooner you know if you carry a Lynch syndrome gene, the more aggressive you can be to prevent cancer.

Not everyone who is diagnosed with Lynch syndrome will get cancer, but everyone with Lynch syndrome carries a higher risk for certain cancers.

Previvor

“Previvor” is the term that describes someone with Lynch syndrome who has NOT been diagnosed with cancer. If you have Lynch syndrome, it is critical to notify all of your doctors so you can follow an aggressive cancer screening and prevention plan.

Read previvor stories in our Champion Stories hub.

Lynch syndrome symptoms

Lynch syndrome itself doesn’t come with any symptoms; but the cancers associated come with a variety of symptoms. Make sure you know the symptoms of colorectal cancer, as well as other cancers Lynch involves, like ovarian and endometrial. Knowing your family’s health history is important because you can pay extra attention to your body for any symptoms that may be associated with Lynch cancers.

Screening guidelines for Lynch syndrome

The NCCN recommends these general screening and risk-reduction guidelines for Lynch syndrome patients:

• Colonoscopy: For individuals with an MLH1 or MSH2 mutation, every one to two years beginning between the ages of 20 to 25, or five years younger than the earliest age at diagnosis in the family (whichever is sooner). For individuals with an MSH6 or PMS2 mutation, every one to three years beginning between the ages of 30 to 35, or five years younger than the earliest age at diagnosis in the family (whichever is sooner).
• Upper endoscopy: Every two to four years starting at age 30-40, in addition to testing for Helicobacter pylori infection at a baseline exam with treatment if positive
• Total body skin examination: Yearly
• Pelvic examination/pelvic ultrasound/endometrial biopsy (women): Every 1-2 years from age 30 to 35 (up until the time of a hysterectomy/oophorectomy)
• Taking a daily aspirin, which may be linked to a reduced risk of colorectal cancer and possibly other cancers in individuals with Lynch syndrome. Before taking aspirin, discuss with your doctor.

You should talk to your doctor for more tailored screening recommendations based on your personal and family history.

Lynch syndrome support 

It’s important to have HOPE, even if you test positive for Lynch syndrome. Many of our relentless champions are living with Lynch, both as survivors and previvors. For support, information and connection with others focused on Lynch syndrome awareness, research, and support, check out our partners:

• AliveAndKickn
• Jacqueline Rush Foundation
• FORCE
• CCARE for Lynch Syndrome

Lynch Syndrome vs HNPCC

Hereditary nonpolyposis colorectal cancer, or HNPCC, is often called Lynch syndrome. Although the two hereditary conditions are very similar, what defines them is what makes them different. Lynch syndrome is defined by have a mutation in a MMR gene, whereas family history criteria are used to make a diagnosis of HNPCC.

How did Lynch syndrome get its name?

Lynch syndrome is named after Dr. Henry Lynch, who devoted his career to studying families that had many people affected with cancer. He described families with Lynch syndrome in the 1970s, at a time when people did not think cancer could be inherited since it isn’t something people are born with. His discoveries have led to increased awareness and prevention of many cancers.