Lynch syndrome & HNPCC

Overview

What is Lynch syndrome?

Lynch syndrome is an inherited condition that causes an increased risk for colorectal cancer and cancer in certain other organs.

How common is Lynch syndrome?

Lynch syndrome occurs in approximately 1 in 400 individuals.

Symptoms and Causes

What causes Lynch syndrome?

Lynch syndrome is caused by a mutation (genetic change) in one of five specific genes that are responsible for fixing errors in DNA. To further explain, DNA are the codes that carry genetic information. Every time cells divide, the DNA duplicates. Sometimes errors occur during DNA duplication that damages cells and affects the way cells grow. A buildup of these damaged cells may lead to cancer. Usually, a gene called the DNA mismatch repair (MMR) gene finds and fixes the errors before they damage the cell. People with Lynch syndrome have a mutation in the MMR gene, which means the errors are less likely to be found and fixed, which increases the risk of developing certain cancers.

Is Lynch syndrome the same as hereditary non-polyposis colorectal cancer (HNPCC)?

Sometimes Lynch syndrome is also referred to as hereditary non-polyposis colorectal cancer (HNPCC), but the two conditions are subtly different.

Lynch syndrome is classified by a mutation in the MMR gene. HNPCC is defined by family history and individuals must meet specific criteria, which are:

  • At least three relatives have colorectal or other HNPCC-related cancers, with one person being a first-degree relative (parent, child, or sibling) of the other two;
  • At least two generations have been affected;
  • At least one person received a diagnosis of colorectal cancer before age 50;
  • Familial adenomatous polyposis has been excluded.

What are the cancer risks associated with Lynch syndrome?

The specific organs at risk for cancer and the degree of increased risk depends on the gene that mutated and, in some cases, if the patient is male or female. The specific genes associated with Lynch syndrome are MLH1, MSH2, MSH6, PMS2, and EPCAM. The list below shows the organs at risk, lifetime risk of developing cancer and average age that cancer is diagnosed.

Cancer type: Colorectal cancer (general population risk is ~5%)

  • Lynch syndrome lifetime risk of cancer
    • MLH1/MSH2 Woman, 22 to 53%; Average age at diagnosis: 27 to 46
    • MLH1/MSH2 Man, 27 to 74%
    • MSH6 Woman, 10 to 18%; Average age at diagnosis: 54 to 63
    • MSH6 Man, 18 to 22%
    • PMS2 Woman, 15%; Average age at diagnosis: 47 to 66
    • PMS2 Man, 20%

Cancer type: Endometrial cancer (women only, general population risk is 2.7%

  • Lynch syndrome lifetime risk of cancer
    • MLH1/MSH2 , 14 to 54%; Average age at diagnosis: 48 to 62
    • MSH6, 17 to 71%; Average age at diagnosis: 54 to 57
    • PMS2, 15%; Average age at diagnosis: 49

Cancer type: Stomach cancer (general population risk is <1%)

  • Lynch syndrome lifetime risk of cancer: 0.2 to 13%
  • Average age at diagnosis: 49 to 55

Cancer type: Ovarian cancer (general population risk is ~1.5%)

  • Lynch syndrome lifetime risk of cancer: 4 to 20%
  • Average age at diagnosis: 43 to 45

Cancer type: Hepatobiliary tract cancer (general population risk is <1%)

  • Lynch syndrome lifetime risk of cancer: 0.02 to 4%
  • Average age at diagnosis: 54 to 57

Cancer type: Urinary tract cancer (general population risk is <1%)

  • Lynch syndrome lifetime risk of cancer: 0.2 to 25%
  • Average age at diagnosis: 52 to 60

Cancer type: Small bowel cancer (general population risk is <1%)

  • Lynch syndrome lifetime risk of cancer: 0.4 to 12%
  • Average age at diagnosis: 46 to 49

Cancer type: Brain/central nervous system cancer (general population risk is <1%)

  • Lynch syndrome lifetime risk of cancer: 1 to 4%
  • Average age at diagnosis: 50

Cancer type: Skin cancer (sebaceous carcinoma, keratoacanthomas, sebaceous adenomas)

  • Lynch syndrome lifetime risk of cancer: 1 to 9%
  • Average age at diagnosis: Unknown

Cancer type: Pancreas cancer (general population risk is ~1.5%)

  • Lynch syndrome lifetime risk of cancer: 0.4 to 4%
  • Average age at diagnosis: 63 to 65

Cancer type: Prostate cancer* (general population risk is ~16%)

  • Lynch syndrome lifetime risk of cancer: 9 to 30%
  • Average age at diagnosis: 59 to 60

Cancer type: Breast cancer* (general population risk is ~12%)

  • Lynch syndrome lifetime risk of cancer: 5 to 18%
  • Average age at diagnosis: 52

*Experts are still unsure whether breast and prostate cancer are part of Lynch Syndrome or not.

The colon cancers caused by Lynch syndrome tend to be more common on the right side of colon and develop much more quickly than in the general population (1 to 2 years versus 10 years). In addition, patients who have a colorectal cancer have a significantly increased risk of developing a second colorectal cancer. This risk is approximately 15 percent within 10 years after the original surgery, 40 percent within 20 years, and 60 percent after 30 years, depending on which surgery is performed.

Some individuals with Lynch syndrome will have a form of the condition called Muir-Torre syndrome. Individuals with Muir-Torre syndrome are prone to develop the cancers listed above as well as benign skin growths (sebaceous adenomas, keratoacanthomas) and skin cancers (sebaceous carcinoma).

Are there other colon risks associated with Lynch syndrome?

Individuals with Lynch syndrome may develop a few colorectal polyps, called adenomas, in the colon or rectum. If these polyps are not detected and removed, they could develop into a cancer. Having regular screening colonscopies is important for detecting and removing these polyps.

Diagnosis and Tests

How is Lynch syndrome diagnosed?

Screening tests and genetic testing are used to diagnose Lynch syndrome. A biopsy of the tumor is used for two screening tests. One test looks for changes that indicate the gene that affects DNA repairs is not working. These changes are called microsatellite instability or MSI. Tumors that have microsatellite instability are called MSI-high (MSI-H). Some 90 to 95 percent of colorectal cancers (and many endometrial cancers) from individuals with Lynch syndrome are MSI-H. This means that the cancer in the family is likely due to Lynch syndrome. However, since about 5 to 10 percent of Lynch syndrome tumors do not show instability, a negative MSI-H test cannot completely rule out the possibility of a Lynch syndrome diagnosis.

There is a second type of screening test for Lynch syndrome that uses a technique called immunohistochemistry (IHC). IHC testing is a screening test done on the tumor that looks for the expression of Lynch syndrome gene products (proteins). If one or more of the proteins are missing in the tumor, it suggests that there is a mutation in that gene, which could then be found through genetic testing. Approximately 88 percent of individuals with Lynch syndrome will have an abnormal IHC result.

Ideally, MSI and/or IHC testing should be done before genetic testing is ordered. However, there are occasions where MSI or IHC cannot be done, in which case genetic testing can be performed. Genetic counseling is recommended before ordering genetic testing. Genetic testing, which involves a blood draw or obtaining a brushing from the inside of the mouth (buccal swab), helps determine if a MLH1, MSH2, MSH6, PMS2, or EPCAM gene mutation is present in the family.

If genetic testing reveals a mutation, a diagnosis of Lynch syndrome is confirmed. Other family members can then be tested. Any other family members who have a mutation would also be at an increased risk for developing cancers associated with Lynch syndrome and should be monitored. If no mutation is found, Lynch syndrome is not necessarily excluded. A genetic counselor can further discuss the meaning of negative genetic test results and cancer risk.

How is Lynch syndrome inherited?

Lynch syndrome is an autosomal dominant disorder. This means that if only one parent carries the mutation for Lynch syndrome, there’s a 50 percent chance a child of the parents will inherit the mutation.

Individuals diagnosed with Lynch syndrome should tell their family members and encourage them to undergo genetic counseling. Counseling includes an evaluation of their personal and family history as well as and genetic testing for the Lynch syndrome gene mutation.

Management and Treatment

How is Lynch syndrome treated?

Currently, there is no cure for Lynch syndrome.

Prevention

Can Lynch syndrome be prevented?

Lynch syndrome is an inherited condition and cannot be prevented. However, patients with Lynch syndrome should undergo lifelong cancer screening beginning in adulthood. The screening recommendations are:

For colorectal cancers:

  • Colonoscopy, starting at age 20, repeated every 1 to 2 years until age 40. Colonoscopy every year after age 40.
  • If cancer is found, colectomy (removing entire colon) should be considered. Continue annual screening for rectal cancer.
  • Prophylactic (preventative) removal of the colon is sometimes considered in cases when colonoscopy cannot be performed.
  • Regular colonoscopy, every 1 to 2 years, for individuals with Lynch syndrome has been proven to decrease the colorectal cancer risk by more than 50 percent.

For endometrial and ovarian cancers:

  • Transvaginal ultrasound and a CA-125 blood test every year beginning at age 30. Unfortunately, screening for ovarian cancer has not been shown to be effective. Therefore, some women with Lynch syndrome consider having a total hysterectomy (removal of the uterus) with salpingo-oophorectomy (removal of both fallopian tubes and ovaries) to eliminate their risk for developing endometrial cancer and to reduce the risk for ovarian cancer. This should be considered after age 35 or once childbearing is complete, whichever is later.

For other cancers:

  • Stomach cancer. Upper endoscopy starting at age 30, with follow up no less than every 3 years.
  • Skin cancer. Annual exam beginning year after diagnosis.
  • Urothelial cancer (bladder, ureters, urethra) cancer or a mutation in the MSH2 gene. Ultrasound repeated every 5 years after diagnosis.
  • Small bowel cancer. Capsule endoscopy starting at age 30, with follow up every 3 years.
  • Urine testing. All patients diagnosed with Lynch syndrome should have a urinalysis every year beginning at age 35.

Are there any other steps that can be taken to reduce the risk of developing the cancers caused by Lynch syndrome?

While aspirin has been shown to reduce risk, the exact dosage of aspirin is still being determined. Therefore, we have not made prescribing this part of our routine practice until dosage information is more fully investigated.

Living With

Who treats patients diagnosed with Lynch syndrome?

It’s highly recommended that individuals diagnosed with Lynch syndrome be managed by clinicians with expertise in treating the condition. Because Lynch syndrome can affect many organ systems, the care team will include a variety of clinicians. Team members may include gastroenterologists, surgeons, gynecologic oncologists, urologists, dermatologists, gynecologists, primary care physicians, geneticists, genetic counselors and oncologists.

Resources

Where can I find more information?

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Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy