MLH1 gene

About 50 percent of all cases of Lynch syndrome with an identified gene mutation are associated with inherited mutations in the MLH1 gene. Several hundred MLH1 gene mutations have been found in people with this condition. Lynch syndrome increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain.

MLH1 gene mutations involved in this condition prevent the production of the MLH1 protein or lead to an altered version of this protein that does not function properly. When the MLH1 protein is absent or nonfunctional, the number of DNA errors that are left unrepaired during cell division increases substantially. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally, increasing the risk of tumor formation in the colon or another part of the body.

Some mutations in the MLH1 gene cause a variant of Lynch syndrome called Turcot syndrome. In addition to colorectal cancer, people with Turcot syndrome tend to develop a particular type of brain tumor called a glioblastoma.

Another variant of Lynch syndrome, called Muir-Torre syndrome, can also be caused by mutations in the MLH1 gene. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, usually on sun-exposed areas of skin.

Inherited changes in the MLH1 gene increase the risk of developing ovarian cancer, as well as other types of cancer, as part of Lynch syndrome (described above). Women with Lynch syndrome have an 8 to 10 percent chance of developing ovarian cancer in their lifetimes, as compared with 1.6 percent in the general population.

While Lynch syndrome is associated with a mutation in one copy of the MLH1 gene, very rarely, individuals in affected families inherit two MLH1 gene mutations, one from each parent. Most often in these cases, the same mutation occurs in both copies of the gene (a homozygous mutation). People with a homozygous MLH1 gene mutation have a syndrome distinct from Lynch syndrome. In addition to colorectal cancer, these individuals may develop cancers of the blood (leukemia or lymphoma). Some of these individuals will also develop characteristic features of a condition known as neurofibromatosis, including noncancerous tumors that grow along nerves (neurofibromas) and light brown patches of skin called café-au-lait spots. The onset of colon cancer in these individuals is extremely early, often occurring during childhood. This syndrome involving colon cancer, leukemia or lymphoma, and neurofibromatosis is sometimes called CoLoN.