EPCAM

Certain variants (also known as mutations) in the EPCAM gene are associated with Lynch syndrome, a condition that increases the risk of developing many types of cancer, particularly cancers of the large intestine (colon) and the rectum (collectively called colorectal cancer). These variants account for up to 3 percent of Lynch syndrome cases. On chromosome 2, the EPCAM gene lies next to another gene called MSH2. Each gene provides instructions for making an individual messenger RNA (mRNA), which serves as the genetic blueprint for making the protein. The EPCAM gene variants involved in Lynch syndrome remove a region that signals the end of the gene, which leads to formation of a long mRNA that includes both EPCAM and MSH2.

For unknown reasons, these EPCAM gene variants cause the MSH2 gene to be turned off (inactivated) by a mechanism known as promoter hypermethylation. The promoter is a region of DNA near the beginning of the gene that controls gene activity (expression). Hypermethylation occurs when too many small molecules called methyl groups are attached to the promoter region. The extra methyl groups attached to the MSH2 promoter reduce the expression of the MSH2 gene, which means that less protein is produced in epithelial cells.

The MSH2 protein plays an essential role in repairing errors in DNA; loss of this protein prevents proper DNA repair, and errors accumulate as the cells continue to divide. These errors can lead to uncontrolled cell growth and increase the risk of cancer.

Variants in the EPCAM gene can also cause congenital tufting enteropathy. This condition is characterized by abnormal development of epithelial cells in the intestines. In this condition, the villi, which are small finger-like projections that line the small intestine, are abnormal. In particular, they have "tufts" of extra epithelial cells on their tips. Normally, these projections provide a greatly increased surface area to absorb nutrients. The altered villi are less able to absorb nutrients and fluids than normal tissue, which causes life-threatening diarrhea and poor growth. Congenital tufting enteropathy develops in newborns within days of birth and lasts throughout life.

People with congenital tufting enteropathy have two copies of the altered EPCAM gene in each cell. These variants lead to an absence of functional EpCAM protein. The resulting loss of EpICD signaling leads to abnormal development of intestinal epithelial cells, causing congenital tufting enteropathy.