MSH2

The MSH2 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 MSH2 protein joins with one of two other proteins, the MSH6 protein or the MSH3 protein, to form an active protein complex. This active protein complex identifies places on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then takes over to help with the actual repair. The MSH2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Lynch syndrome - increased risk from variations of the MSH2 gene

About 40 percent of all cases of Lynch syndrome with an identified gene mutation are associated with mutations in the MSH2 gene. Several hundred MSH2 mutations that predispose people to colorectal cancer and other HNPCC-associated cancers have been found. These mutations may cause the production of an abnormally short or inactivated MSH2 protein that cannot perform its normal function. When the MSH2 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 mutations in the MSH2 gene have an increased risk 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, brain, and skin.

Some mutations in the MSH2 gene increase the likelihood of several uncommon skin tumors occurring in addition to colorectal cancer, a combination called Muir-Torre syndrome. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in skin glands (sebaceous glands) that produce an oily substance called sebum. Multiple, rapidly growing skin tumors called keratoacanthomas may also occur, usually on sun-exposed areas.

other cancers - caused by mutations in the MSH2 gene

Some individuals in families affected by Lynch syndrome have a mutation in both copies of the MSH2 gene. Most often, the same mutation occurs in both copies of the gene (a homozygous mutation) in each cell. People with a homozygous MSH2 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.