Lynch syndrome is a genetic condition associated with an increased risk of cancer. Lynch syndrome is formerly known as "hereditary nonpolyposis colorectal cancer syndrome" (HNPCC). Individuals with Lynch syndrome are more likely to develop colorectal, uterine cancer, and other types. 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.

The condition is caused by a mutation in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2.  Mutations in EPCAM can also cause Lynch syndrome as EPCAM is connected to MSH2. The MMR genes are like spellcheckers, they repair errors that occur when DNA copies itself. However, when the spellchecker itself is broken, the DNA doesn't get corrected, and more and more errors start to accumulate in the genetic code.

Several hundred mutations in the MMR genes that predispose people to colorectal cancer and other Lynch syndrome-associated cancers have been found. These mutations may cause the gene to produce abnormal protein or no protein at all. When this happens, the gene cannot perform its normal function. When the mismatch repair protein is absent or ineffective, the number of mistakes that are left unrepaired during cell division increases substantially. If the cells continue to divide, errors accumulate in the rest of the DNA, and the cells become unable to function properly and may form a tumor in the colon, endometrium or another part of the body.

Lynch syndrome is the most common form of hereditary colorectal cancer. The prevalence of Lynch syndrome is estimated to be approximately 1 in 370. This means that approximately 1 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 EPCAM 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.

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. 

Here’s how it works: Every person has two copies of each of the five 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 a person's 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 higher lifetime risk and their average age at diagnosis is about 45 years. Some data indicates that the cumulative colorectal cancer incidence for those with Lynch syndrome (all mutations) 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 higher 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 greater lifetime risk of developing stomach cancer and ovarian cancer.³

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

Constitutional Mismatch Repair Deficiency

Constitutional Mismatch Repair Deficiency (CMMRD) (aka Biallelic Mismatch Repair Deficiency or Homozygous Mismatch Repair Mutations) is a hereditary cancer predisposition that typically presents in infancy, childhood or young adulthood. Individuals with CMMRD are at risk for developing hematologic malignancies, brain tumors, colon, small bowel, uterine, gastric, urologic and other types of cancer. Individuals with CMMRD have an estimated a 16-fold increased risk for persons with biallelic MSH2 mutations. They can have multiple diagnoses of these cancers throughout their life.  Additionally, café au lait macules have been reported in these individuals.

CMMRD is caused by mutations in the Mismatch Repair (MMR) genes:  MLH1, MSH2, MSH6 and PMS2.  When a person has one mutation in one of their MMR gene then they have Lynch syndrome. A person must have 2 gene mutations in the same MMR gene to develop CMMRD. For example, if both their mother and father had one mutation in their PMS2 genes they would have to inherit both their mother’s and father’s mutated copy. Couples who each carry a single gene mutation in the same MMR gene have a 1 in 4 or 25% risk to have a child with CMMRD.  We recommend couples who each carry a MMR gene mutation in the same MMR gene see a genetic counselor who specializes in prenatal genetics either during or prior to pregnancy to discuss available testing options and to learn more about this condition.

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.