Hereditary nonpolyposis colorectal cancer; ... Lynch syndrome (Hereditary nonpolyposis colorectal cancer -HNPCC-; Lynch syndrome) - Genes MLH1, MSH2, MSH6, PMS2, or EPCAM.

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many cancers, particularly colorectal cancer. People with Lynch syndrome also have an increased risk of developing stomach cancer, small intestine, liver, gall bladder, upper urinary tract, brain and skin. In addition, affected women are at high risk of ovarian and endometrial cancer. Sometimes, people with Lynch syndrome can develop colon polyps.

This process is due to variations in the MLH1, MSH2, MSH6, PMS2 and EPCAM genes. MLH1 genes, located on the short arm of chromosome 3 (3p21.3), MSH2, located on the short arm of chromosome 2 (2p21), MSH6, located on the short arm of chromosome 2 (2p16) and PMS2, located in the short arm of chromosome 7 (7p22.2) are involved in the repair of errors that occur when DNA is copied in preparation for cell division. Repairs are made by removing the DNA sequence contains errors and replacing a DNA sequence corrected.

Approximately 50% of all cases of Lynch syndrome are associated with mutations in the MLH1 gene, 40% mutations in MSH2 gene, 10% mutations in MSH6 gene and 2% of cases with mutations in the PMS2 gene. Mutations in any of these genes prevent the proper repair errors in the DNA copy. As abnormal cells continue to divide, cumulative errors can lead to uncontrolled cell growth and possibly cancer. Some mutations in MLH1, MSH2 , and MSH6 genes give rise to a variant of Lynch syndrome called syndrome Muir-Torre. A part of colorectal cancer, people with this condition have an increased risk of developing several rare tumors of the skin. These rare skin tumors include carcinomas sebaceous adenomas and which occur in the sebaceous glands. Multiple Keratoacanthomas may also appear, usually in sun - exposed areas of skin. In addition, some mutations in MLH1 and PMS2 genes can cause a variant of Lynch syndrome called Turcot further wherein colorectal cancer affected people develop a glioblastoma syndrome.

The EPCAM gene, located on the short arm of chromosome 2 (2p21), encodes a protein known as epithelial cell adhesion molecule (EpCAM). This protein is found in the membrane of epithelial cells, where it contributes to cell adhesion. In addition, the protein in the cell membrane may be cleaved at a specific location, releasing a fragment denominad intracellular domain (EpICD), that helps convey signals from outside the cell to the cell nucleus. EpICD moves to the nucleus and binds to other proteins, forming a complex that regulates the activity of several genes that are involved in growth, proliferation, differentiation and cell migration.

Mutations in the gene EPCAM represent up to 6% of cases of Lynch syndrome. On chromosome 2, the EPCAM gene is by the MSH2 gene. Each gene encodes mRNA which serves as the genetic blueprint for the production of the protein. Mutations in genes involved EPCAM Lynch syndrome eliminate a region that signals the end of the gene, leading to the formation of a long mRNA which includes both EPCAM as MSH2. For unknown reasons, these mutations cause the EPCAM gene Msh2 is inactivated by gene a mechanism known as promoter hypermethylation. Hypermethylation occurs when the methyl groups are attached to the promoter region. Additional methyl groups attached to the promoter MSH2 reduce expression of MSH2 gene, which means that less protein is encoded in epithelial cells. MSH2 protein plays an essential role in repairing DNA errors, so the 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.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to increase the risk of cancer. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit mutations in these genes will develop cancer.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with HNPCC or nonpolyposis hereditary colorectal cancer (HNPCC), by complete PCR amplification of the exons of the MLH1, MSH2, MSH6, PMS2 and EPCAM genes, respectively and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).