MLH1

The MLH1 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein fixes mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein, the PMS2 protein, to form an active protein complex. This protein complex coordinates the activities of other proteins that repair mistakes made during DNA replication. The repairs are made by removing a section of DNA that contains mistakes and replacing the section with a corrected DNA sequence. The MLH1 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Lynch syndrome - increased risk from variations of the MLH1 gene

About 50 percent of all cases of Lynch syndrome with an identified gene mutation are associated with mutations in the MLH1 gene. Several hundred MLH1 mutations that predispose people to colorectal cancer have been found. These mutations prevent the production of MLH1 protein or lead to an altered version of this protein that does not function properly. When the MLH1 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 DNA; the cells become unable to function properly and may form a tumor in the colon or another part of the body.

People with a mutation in this gene also have an increased chance of developing several other types of cancer, including cancers of the endometrium (lining of the uterus), ovary, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain.

Mutations in the MLH1 gene sometimes 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.

other cancers - caused by mutations in the MLH1 gene

Some individuals in families affected by Lynch syndrome have a mutation in both copies of the MLH1 gene. Most often, the same mutation occurs in both copies of the gene (a homozygous mutation) in each cell. People with a homozygous MLH1 mutation have a syndrome distinct from Lynch syndrome. In addition to colorectal cancer, they may develop cancers of the blood (leukemia or lymphoma). Some of these individuals will also develop noncancerous tumors that grow along nerves (neurofibromas) and have light brown patches of skin called café-au-lait spots. These two signs are characteristic of a condition known as neurofibromatosis. 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.