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EPCAM
epithelial cell adhesion molecule
The EPCAM gene provides instructions for the epithelial cell adhesion molecule, a protein essential for cell-to-cell adhesion and critical signalling pathways involved in cell growth, division, and differentiation. The EPCAM gene encodes a protein integral to epithelial cell function, facilitating cell adhesion and communication.
EPCAM is located on the short (p) arm of chromosome 2, at band 2p21. Arm ratio per GRCh38 - banding schematic.
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Overview
The EPCAM gene, full name epithelial cell adhesion molecule, plays a vital role in maintaining the integrity and function of epithelial tissues throughout the body. The protein produced from this gene is involved in cell-to-cell adhesion and intracellular signalling. It is generally found spanning the cell membrane of epithelial cells.
Pathogenic variants in the EPCAM gene can disrupt these fundamental cellular processes, leading to a range of health conditions. These conditions primarily affect the gastrointestinal system and can also increase the risk of developing certain cancers.
What the gene does
The EPCAM gene directs the synthesis of the epithelial cellular adhesion molecule (EpCAM) protein, which is primarily located within the cell membrane of epithelial cells. This protein helps these cells adhere to one another, a crucial function for maintaining tissue structure and integrity.
Beyond its role in cell adhesion, the EpCAM protein also participates in intracellular signalling. A specific region of the protein can be cleaved when it is located in the cell membrane, releasing a segment known as the intracellular domain (EpICD). This EpICD then travels into the cell's nucleus.
Within the nucleus, EpICD interacts with other proteins, forming a complex that regulates the activity of several genes. These genes are involved in essential cellular processes, including growth, division (proliferation), maturation (differentiation), and movement (migration). These processes are fundamental for proper cell and tissue development and function.
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Chromosome location
The EPCAM gene is located on chromosome 2 at position 2p21. This specific genomic address indicates its precise place within the human genome. The gene's location is important for understanding how its variants might be inherited or interact with other genetic factors.
Protein structure
The EPCAM protein consists of 314 amino acids. It features a Thyroglobulin type-1 domain, spanning amino acids 63-135. This domain is integral to the protein's overall structure and function, particularly in its role in cell adhesion and signalling.
Key variants
Variants within the EPCAM gene can impact its ability to produce a functional epithelial cell adhesion molecule. These genetic changes can range from small alterations, such as single nucleotide changes, to larger deletions affecting parts of the gene. Such variants can disrupt the protein's structure, alter its cellular location, or impair its ability to interact with other proteins or regulate gene expression.
The specific effects of an EPCAM variant depend on its nature and location within the gene. Pathogenic variants can lead to a loss of normal protein function, contributing to the development of associated genetic conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.13C>T | p.Gln5Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital diarrhea 5 with tufting enteropathy |
c.227C>G | p.Ser76Ter | Pathogenic | ★★☆☆ | Congenital diarrhea 5 with tufting enteropathy |
c.265C>T | p.Gln89Ter | Pathogenic | ★★☆☆ | Congenital diarrhea 5 with tufting enteropathy |
c.373_374insC | p.Arg125fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital diarrhea 5 with tufting enteropathy |
c.491+1G>A | - | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.492-2A>G | - | Pathogenic | ★★☆☆ | EPCAM-related disorders |
c.499dup | p.Gln167fs | Pathogenic | ★★☆☆ | EPCAM-related disorders |
c.556-14A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | EPCAM-related disorders |
c.73G>T | p.Glu25Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
g.(47607109_47612304)_(47613753_?)del | - | Pathogenic | ★☆☆☆ | Hereditary nonpolyposis colon cancer |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the EPCAM gene are associated with several inherited conditions. One such condition is Tufting enteropathy, which is inherited in an autosomal recessive pattern. This condition is characterised by abnormal development of epithelial cells within the intestines.
Additionally, certain EPCAM variants are linked to an increased risk of developing Lynch syndrome. Lynch syndrome is a hereditary cancer predisposition syndrome, primarily increasing the risk for colorectal cancer and other types of cancer. While EPCAM variants account for a smaller percentage of Lynch syndrome cases, their presence can significantly influence an individual's cancer risk.
Inheritance pattern
Conditions caused by pathogenic EPCAM variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The EPCAM gene is included on several panels within the NHS Genomic Medicine Service, reflecting its clinical significance in the UK. It is assessed for its role in conditions such as Adult solid tumours cancer susceptibility, Adult solid tumours for rare disease, and Gastrointestinal epithelial barrier disorders. The gene also features on panels related to GI tract tumours, Infantile enterocolitis & monogenic inflammatory bowel disease, Inherited MMR deficiency (Lynch syndrome), Inherited polyposis and early onset colorectal cancer, and Intestinal failure or congenital diarrhoea. The gene is classified as 'green' on these panels, indicating that variants in EPCAM are considered to be of diagnostic or clinical significance.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
While specific lifestyle modifications cannot alter the fundamental genetic effects of EPCAM gene variants, maintaining a healthy lifestyle is generally recommended for overall well-being. A balanced diet, rich in fruits, vegetables, and whole grains, combined with regular physical activity, supports general health. For individuals with conditions like Lynch syndrome, research suggests that certain lifestyle factors, such as maintaining a healthy weight and avoiding smoking, may contribute to overall health. However, these general recommendations are not specific treatments for genetic conditions.
Supplement considerations
There is currently no conclusive evidence to suggest that specific supplements can prevent or treat conditions associated with EPCAM gene variants. For individuals with conditions linked to EPCAM, any decisions regarding supplement use should be made in consultation with a healthcare professional. A healthcare provider can offer personalised advice, considering an individual's specific health status and potential interactions with other medications or existing health conditions.
Frequently asked questions
What is the primary function of the EPCAM protein?
The EPCAM protein is primarily involved in cell-to-cell adhesion, helping epithelial cells stick together. It also plays a role in intracellular signalling, influencing processes like cell growth, division, and differentiation.
Which conditions are associated with EPCAM gene variants?
Variants in the EPCAM gene are associated with Tufting enteropathy, an autosomal recessive condition affecting the intestines, and an increased risk of Lynch syndrome, which predisposes individuals to certain cancers, particularly colorectal cancer.
Is EPCAM associated with cancer risk?
Yes, certain variants in the EPCAM gene are associated with an increased risk of developing Lynch syndrome, a hereditary condition that significantly raises the risk for various cancers, especially colorectal cancer.
How is Tufting enteropathy inherited?
Tufting enteropathy, a condition linked to EPCAM gene variants, is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
What does 'epithelial cell adhesion molecule' mean?
It refers to a protein found on the surface of epithelial cells, which are cells that line body surfaces and cavities. This protein helps these cells stick to one another, contributing to tissue structure and integrity.
References
- Tamura K, Kaneda M, Futagawa M. Correction to: Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. International journal of clinical oncology. 2019. PMID: 31368001
- Schnell U, Kuipers J, Mueller JL. Absence of cell-surface EpCAM in congenital tufting enteropathy. Human molecular genetics. 2013. PMID: 23462293
- Kuiper RP, Vissers LE, Venkatachalam R. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Human mutation. 2011. PMID: 21309036
- Ligtenberg MJ, Kuiper RP, Chan TL. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nature genetics. 2009. PMID: 19098912
- Maetzel D, Denzel S, Mack B. Nuclear signalling by tumour-associated antigen EpCAM. Nature cell biology. 2009. PMID: 19136966
- Niessen RC, Hofstra RM, Westers H. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes, chromosomes & cancer. 2009. PMID: 19455606
- Sivagnanam M, Mueller JL, Lee H. Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology. 2008. PMID: 18572020
- Adam MP, Bick S, Mirzaa GM. Lynch Syndrome. 1993. PMID: 20301390