epithelial cell adhesion molecule
The EPCAM gene provides instructions for making a protein known as epithelial cellular adhesion molecule (EpCAM). This protein is found in epithelial cells, which are the cells that line the surfaces and cavities of the body. The EpCAM protein is found spanning the membrane that surrounds epithelial cells, where it helps cells stick to one another (cell adhesion). In addition, the protein in the cell membrane can be cut at a specific location, releasing a piece called the intracellular domain (EpICD), which helps relay signals from outside the cell to the nucleus of the cell. EpICD travels to the nucleus and associates with other proteins, forming a group (complex) that regulates the activity of several genes that are involved in cell growth and division (proliferation), maturation (differentiation), and movement (migration), all of which are important processes for the proper development of cells and tissues.
Certain 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 mutations account for up to 6 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 mutations 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 mutations 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 mistakes in DNA; loss of this protein prevents proper DNA repair, and mistakes accumulate as the cells continue to divide. These mistakes can lead to uncontrolled cell growth and increase the risk of cancer.
Mutations 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. EPCAM gene mutations involved in this condition lead to the loss of functional EpCAM protein. The resulting loss of EpICD signaling leads to abnormal development of intestinal epithelial cells, causing congenital tufting enteropathy.
- epithelial cell adhesion molecule precursor
- epithelial glycoprotein 314
- human epithelial glycoprotein-2
- tumor-associated calcium signal transducer 1
- American Medical Association and National Coalition for Health Professional Education in Genetics: Understand the Basics of Genetic Testing for Hereditary Colorectal Cancer (PDF)
- Holland-Frei Cancer Medicine (sixth edition, 2003): DNA Mismatch Repair Gene Defects and HNPCC
- Molecular Biology of the Cell (fourth edition, 2002): Defects in DNA Mismatch Repair Provide an Alternative Route to Colorectal Cancer