What's Lynch Syndrome

Lynch syndrome is a genetic condition associated with an increased risk of cancer. Lynch syndrome is sometimes referred to as hereditary nonpolyposis colorectal cancer syndrome (HNPCC). Individuals with Lynch syndrome are more likely to develop colorectal and/or uterine cancer and the cancers are also more likely to occur at a younger age than usual. Although Lynch syndrome is primarily associated with colorectal and uterine cancers, it has also been associated with an increased risk of ovarian cancer and cancers of the small intestine, urinary tract, hepatobiliary tract, skin, and brain.

Lynch syndrome is the most common type of hereditary colorectal cancer syndrome. It is estimated that the prevalence of Lynch syndrome is approximately one in 370. This means that approximately one out of 370 people are affected with Lynch syndrome.

What causes Lynch syndrome?

Lynch syndrome is a hereditary condition caused by a genetic change called a mutation.

A gene is a hereditary unit of DNA that occupies a specific location on a chromosome. Genes carry directions to cells and tell them to make specific proteins that perform and regulate all body functions. Genes are capable of replicating themselves at each cell division. A mutation is a change in the usual DNA sequence of a particular gene. Mutations can be beneficial, harmful, or neutral. Many diseases, including cancer, begin in the genes. Genetic mutations can be inherited from a parent or can be random mutations that occur as a result of a mistake during cell division or in response to environmental factors.

There are four major genes involved in the development of Lynch syndrome: MLH1, MSH2, MSH6, and PMS2. The majority of cases of Lynch syndrome are the result of mutations in either the MLH1 or MSH2 genes; however, mutations in the MSH6, PMS2, or other genes can also cause Lynch syndrome.

An inherited mutation in one of these genes means that the body is not able to properly repair DNA. Put simply, there is a mistake in a gene that normally helps prevent cancer—which is why Lynch syndrome is associated with a higher risk of some cancers.

In 2009, a new gene—EPCAM—was discovered to cause Lynch syndrome. Although it is not one of the mismatch repair genes (MLH1, MSH2, MSH6 or PMS2), it does cause the MSH2 gene to not be expressed. Individuals with EPCAM mutations often have colon or endometrial tumors that show a loss of the MSH2 and MSH6 proteins. Additionally, genetic testing for the MSH2 and MSH6 gene will be negative, meaning no mutation found. It is estimated that 30% of individuals who have a loss of MSH2/MSH6 in their tumor and have negative gene testing for MSH2 and MSH6 have a mutation in EPCAM.

What are the chances of inheriting Lynch syndrome?

There is a 50 percent chance that a person with Lynch syndrome will pass the mutation on to their children. Lynch syndrome does not skip generations and it affects males and females equally. This is called autosomal dominant inheritance. To read more about inheritance click here.

Here’s how it works: Every person has two copies of each of the four Lynch syndrome genes—one copy inherited from the mother and one copy inherited from the father. An inherited mutation in either of these copies will cause Lynch syndrome. In other words, someone who has one normal Lynch syndrome gene and one mutated Lynch syndrome gene will have Lynch syndrome. When someone with Lynch syndrome has a child, he/she may pass on the normal gene or the mutated gene—meaning that the child has a 50 percent chance of either a) inheriting the Lynch syndrome gene mutation, which means an increased likelihood for developing colorectal or uterine cancer or b) inheriting the normal gene, which means an average risk for developing cancer (the same as the general population).

Cancer Risk and Lynch Syndrome

Lynch syndrome is not a guarantee of developing cancer, but it does increase the risk.

Colorectal Cancer: Individuals with Lynch syndrome have a higher-than-average risk of developing colorectal cancer and they tend to develop it at a younger age. The average lifetime risk for developing colorectal cancer is approximately 6 percent; however, individuals with Lynch syndrome have a lifetime risk of 60-80 percent and their average age at diagnosis is about 45 years. Some data indicates that the cumulative colorectal cancer incidence for those with Lynch syndrome is 82 percent. Individuals with Lynch syndrome also have an increased risk of developing a second primary colorectal cancer.

Uterine Cancer: The average lifetime risk of developing uterine cancer is about 3 percent; however, women with Lynch syndrome have a 40-60 percent lifetime risk of developing uterine cancer.3

Other cancers: Some other cancers associated with Lynch syndrome are cancers of the ovary, small intestine, urinary tract, hepatobiliary tract, skin, and brain. Individuals who have sebaceous gland skin tumors (sebaceous adenomas, sebaceous carcinomas, epitheliomas, keratoacanthomas) are often referred to as having the Muir-Torre variant of Lynch syndrome. Individuals with Lynch syndrome have a 12 percent lifetime risk of developing stomach cancer and a 13 percent lifetime risk of developing ovarian cancer.3

 

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If you have questions and would like to speak to a genetic counselor about Lynch syndrome please either contact the Kintalk UCSF genetic counselors or you can find a cancer genetic counselor near you on the National Society of Genetic Counselors or the NCI Cancer Genetics Services Directory.

Next Section: Diagnosing Lynch Syndrome»

 

References:
1 de la Chapelle A. The incidence of Lynch syndrome. Familial Cancer. 2005; 4(3): 233-7.
2 Lynch HT, de la Chapelle A. Hereditary Colorectal Cancer. New England Journal of Medicine. 2003; 348:919-932.
3 Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer. 1999; 81(2): 214-8.