Lynch syndrome is estimated to occur in 1 in 280 to 440 individuals. It is the cause of up to 3% of colorectal cancers and 2% of endometrial cancers.
Family History of Cancer
A diagnosis of Lynch syndrome may be suspected based on a family history of cancer. The types of cancer, number of relatives and generations affected with cancer, and age of onset of cancer in the family can help identify someone or a family at risk of a hereditary colon cancer syndrome (Table 1).
The Amsterdam I Criteria:
- Three or more relatives with colorectal cancer, one of whom is a first-degree relative (mother, father, sister, brother, daughter, or son) of the other two
- Two or more generations with colorectal cancer
- At least one individual with colorectal cancer in the family who was diagnosed before age 50
- The family does not have a different inherited colorectal cancer condition called “familial adenomatous polyposis”
Amsterdam II Criteria:
- Three or more relatives with HNPCC-associated cancers (colorectal, endometrial, small bowel, ureter, or renal pelvis) cancer, one of whom is a first-degree relative of the other two
- Two or more generations with the above cancer(s)
- At least one individual with the above cancer(s) in the family who was diagnosed before age 50
- The family does not have a different inherited colorectal cancer genetic condition called “familial adenomatous polyposis”
About 50% of families who meet the Amsterdam I or Amsterdam II Criteria have Lynch syndrome, meaning they have a mutation in the Lynch syndrome genes MLH1, MSH2, MSH6, PMS2, or EPCAM.
Importantly, many people with Lynch syndrome do not meet Amsterdam I or II criteria. The diagnosis of Lynch syndrome may be suspected if someone is diagnosed with a colorectal or endometrial cancer before the age of 50 or if a person has been diagnosed with more than one of the Lynch syndrome-related cancers.
Family History of Lynch Syndrome
The greatest risk factor for having Lynch syndrome is having a relative with this condition. The first-degree relatives of an individual with Lynch syndrome (mother/father, brothers/sisters, and children) have a 50% chance of having the same mutation. Depending on who else in the family has inherited the mutation, more extended relatives such as aunts/uncles, grandparents, grandchildren, and cousins could also have Lynch syndrome.
As an example, Suzie is a 46-year-old woman with colon cancer due to a mutation in the MSH2 gene causing Lynch syndrome. She has two daughters. Her brother has two sons. Both of her parents are still living. Her brother undergoes genetic testing for Suzie’s MSH2 mutation (see below) and does not have it. Therefore, he does not have Lynch syndrome and his two children are not at risk of Lynch syndrome. Both of Suzie’s daughters are tested, and one is found to have the MSH2 mutation. This daughter has Lynch syndrome. She has a 50% chance to pass the mutation on to her children. Her other daughter is negative for the MSH2 mutation. Neither she nor her children are at risk of Lynch syndrome. Suzie’s mother and father are tested and her father is found to have the same mutation as Suzie. Suzie’s maternal relatives, therefore, do not have a risk of having Lynch syndrome. Suzie’s father’s brothers and sisters have a 50% chance of inheriting Lynch syndrome, and need to be tested for Suzie’s mutation in order to determine if they also have Lynch syndrome and if their children also have a risk of having Lynch syndrome.
Screening Tests for Lynch Syndrome
The best approach to make the diagnosis of Lynch syndrome is by testing a colorectal cancer for genetic alterations seen in Lynch syndrome.
Lynch syndrome results in damage to genetic areas of DNA called “microsatellites.” A high level of microsatellite damage (“MSI-H”) is a sign of Lynch syndrome. Approximately 90-95% of colorectal cancers caused by Lynch syndrome will be MSI-H. Another tumor test for Lynch syndrome includes immunohistochemistry (IHC). IHC colors the proteins produced by genes. A mutation in a Lynch syndrome gene will result in a lack of staining of the corresponding protein. Approximately 88% of colorectal cancers caused by Lynch syndrome will have an abnormal IHC result.
At some medical centers, all patients with colorectal and/or endometrial cancer will automatically have tests of their cancer done to evaluate for Lynch syndrome. This is called universal testing.
Genetic or “Germline” Testing
If someone has a compelling personal or family history of cancer, or abnormal MSI/IHC results suspicious for Lynch syndrome, “germline” genetic testing should be considered. Germline testing is typically done on a blood or saliva sample. The testing is most often covered by insurance. Genetic test results can take anywhere from 2 weeks to 3 months to complete. One of the following three results will be found on germline testing:
- “Positive” or abnormal: This confirms that the individual has Lynch syndrome. This also allows the healthcare provider to offer genetic testing to other family members.
- “Negative” or normal: This means that no Lynch syndrome mutation was found. This negative result could mean a few different things, depending upon whether the patient was the one with cancer, a relative of someone with cancer, or a relative of someone with known Lynch syndrome:
- The cancer in the family is not due to Lynch syndrome.
- There is a harmful mutation in the gene(s) that could not be found with current genetic testing technology.
- There is a harmful mutation in another gene that was not tested.
- “Uncertain” or variant of uncertain significance (VUS): A VUS is a genetic alteration that is not established if it leads to disease or has no health consequences. A VUS can neither confirm nor deny the diagnosis of Lynch syndrome. It should not be used to test other relatives or determine what type of cancer screening a person needs.
Genetic testing can be a complex process. Additionally, it can raise medical, emotional, familial, social, financial, legal, and ethical concerns for people at risk of, suspected of, or diagnosed with Lynch syndrome. It is recommended that individuals pursuing genetic testing have pre- and post-test genetic counseling by an appropriately trained healthcare professional. This might include a genetic counselor or medical geneticist. During a pre-testing genetic counseling visit, the healthcare provider will collect a medical and family history to determine if genetic testing, is appropriate. The healthcare provider will educate the patient about Lynch syndrome cancer risks, management options, inheritance patterns, the genetic testing process, and support and counseling related to emotional concerns. Importantly, information will be shared about insurance coverage and costs for genetic testing, protections against genetic discrimination, and a plan for how test results will be shared with the patient and family members. Upon completion of genetic testing, the healthcare provider will provide an interpretation of the genetic test results and help the patient understand the implications for their health, as well as for his or her family members. The National Society of Genetic Counselors (www.nsgc.org) has a search feature to find a genetic counselor near his or her home. For individuals who do not have a genetic counselor in their area, there are telephone genetic counseling services available from companies such as InformedDNA (informeddna.com).