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CDH1
cadherin 1
The CDH1 gene provides instructions for producing the E-cadherin protein, which is crucial for cell adhesion, tissue organisation, and acts as a tumour suppressor. The CDH1 gene encodes E-cadherin, a protein vital for cell-to-cell adhesion in epithelial tissues throughout the body.
CDH1 is located on the long (q) arm of chromosome 16, at band 16q22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The CDH1 gene, also known as cadherin 1, is a crucial component of human genetics, providing instructions for the E-cadherin protein. This protein is predominantly found in epithelial cells, which form the linings of organs and body surfaces. E-cadherin acts as a molecular 'glue', ensuring that cells adhere properly to each other, forming robust and organised tissues.
Beyond its adhesive properties, E-cadherin participates in intracellular communication, influencing cell maturation, movement, and the regulation of gene activity. It also functions as a tumour suppressor, helping to prevent the uncontrolled growth and division of cells. Understanding the CDH1 gene's role is therefore essential for comprehending normal tissue development and cancer predisposition.
What the gene does
The E-cadherin protein, encoded by the CDH1 gene, is a key cell surface protein belonging to the cadherin family. Its primary function involves mediating calcium-dependent cell-to-cell adhesion, which is fundamental for the formation and maintenance of organised tissues, particularly epithelia. E-cadherin molecules on adjacent cells bind to each other, creating strong junctions that help maintain tissue integrity and structure. This adhesive property is critical for various biological processes, including embryonic development, wound healing, and maintaining the barrier function of epithelia.
In addition to its structural role, E-cadherin is involved in transmitting biochemical signals within cells. These signals influence cellular processes such as proliferation, differentiation, and migration. The protein's interaction with p120-catenin, encoded by the CTNND1 gene, is important for stabilising E-cadherin at the cell membrane and preventing its premature degradation. This interaction is thought to be particularly important for normal craniofacial development. Furthermore, E-cadherin acts as a tumour suppressor protein, meaning it helps to regulate cell growth and division, preventing the uncontrolled proliferation characteristic of cancer.
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Chromosome location
The CDH1 gene is located on the long arm of chromosome 16, specifically at band 16q22.1. This precise genomic address helps geneticists and clinicians pinpoint its position within the human genome. Genes located on chromosome 16 are involved in a wide array of biological processes, and their study contributes to understanding both normal physiological functions and various inherited conditions.
Protein structure
The E-cadherin protein, comprised of 882 amino acids, exhibits a well-defined domain structure essential for its function. It features five key cadherin domains: Cadherin 1 (amino acids 155-262), Cadherin 2 (amino acids 263-375), Cadherin 3 (amino acids 376-486), Cadherin 4 (amino acids 487-593), and Cadherin 5 (amino acids 594-697). These extracellular domains are crucial for the calcium-dependent cell-to-cell adhesion activity of the protein.
Towards the C-terminus, a disordered region (amino acids 747-767) suggests flexibility important for protein interactions. Specific segments are identified as crucial for binding other proteins: amino acids 758-769 are required for binding CTNND1 and PSEN1, while the region spanning amino acids 811-882 is required for binding alpha, beta, and gamma catenins. These intracellular interactions are vital for linking E-cadherin to the actin cytoskeleton and for its signalling functions.
Key variants
Variants within the CDH1 gene can impact the function of the E-cadherin protein, potentially leading to a range of health outcomes. These genetic alterations can include small changes to DNA building blocks (single nucleotide variants) or larger structural changes, such as deletions or duplications. The nature and location of a variant often determine its effect on protein function, which can range from minor impact to complete loss of function. Understanding the specific type and consequence of CDH1 variants is crucial for assessing potential health risks.
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.1003C>T | p.Arg335Ter | Pathogenic | ★★★☆ | Hereditary diffuse gastric adenocarcinoma |
c.1008G>A | p.Glu336= | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1009_1010del | p.Ser337Phefs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1023T>G | p.Tyr341Ter | Pathogenic | ★★★☆ | Hereditary diffuse gastric adenocarcinoma |
c.1031_1032dup | p.Val345fs | Pathogenic | ★★★☆ | not provided |
c.1051C>T | p.Gln351Ter | Pathogenic | ★★★☆ | Hereditary diffuse gastric adenocarcinoma |
c.1064del | p.Gly354_Leu355insTer | Pathogenic | ★★★☆ | Hereditary diffuse gastric adenocarcinoma |
c.1085del | p.Val362fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1107del | p.Asn369fs | Pathogenic | ★★★☆ | Hereditary diffuse gastric adenocarcinoma |
c.1131del | p.Thr378fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
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
Pathogenic variants in the CDH1 gene are primarily associated with Hereditary diffuse gastric cancer, an inherited condition characterised by a significantly increased risk of developing diffuse-type stomach cancer. Such variants also increase the risk of lobular breast cancer in women. Other conditions, including Blepharocheilodontic syndrome, a congenital disorder affecting facial development, and some cases of ovarian and prostate cancer, have also been linked to CDH1 variants.
Inheritance pattern
Conditions caused by pathogenic CDH1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the CDH1 gene is recognised within the NHS Genomic Medicine Service due to its clinical significance. It is included on several NHS England National Genomic Test Directory panels, indicating its importance in diagnostic testing for various conditions. These panels include Adult solid tumours cancer susceptibility, Adult solid tumours for rare disease, Clefting, DDG2P, Familial breast cancer, Foetal anomalies (R21), and Hereditary diffuse gastric cancer (R215). This inclusion ensures that testing for CDH1 variants is available for individuals meeting specific clinical criteria.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle, including a balanced diet and regular physical activity, is generally recommended for overall well-being. For individuals with CDH1 variants, avoiding smoking and excessive alcohol consumption may be particularly relevant, as these factors are known to increase cancer risk in the general population. Research suggests that a diet rich in fruits, vegetables, and whole grains may contribute to general health, but there is no conclusive evidence that specific lifestyle interventions can prevent the onset of conditions associated with CDH1 variants.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat conditions associated with CDH1 gene variants. While various supplements are promoted for general health, individuals should always discuss any plans to take supplements with a healthcare provider. This is important to ensure their safety and to avoid potential interactions with medications or existing health conditions.
Frequently asked questions
What is the primary function of the CDH1 gene?
The CDH1 gene provides instructions for making the E-cadherin protein, which is essential for cell-to-cell adhesion in epithelial tissues. This protein helps cells stick together to form organised tissues and also acts as a tumour suppressor.
What health conditions are associated with CDH1 gene variants?
Pathogenic variants in the CDH1 gene are primarily associated with Hereditary diffuse gastric cancer. They also increase the risk of lobular breast cancer and have been linked to Blepharocheilodontic syndrome, as well as some cases of ovarian and prostate cancer.
How does E-cadherin prevent cancer?
E-cadherin acts as a tumour suppressor by regulating cell growth and division. It helps maintain normal tissue architecture and cellular communication, preventing uncontrolled cell proliferation which is a hallmark of cancer development.
Is CDH1 testing available in the UK?
Yes, the CDH1 gene is included on several NHS England National Genomic Test Directory panels, such as those for Adult solid tumours cancer susceptibility, Familial breast cancer, and Hereditary diffuse gastric cancer. This indicates its availability for diagnostic testing under specific clinical criteria.
Can lifestyle changes prevent conditions associated with CDH1 variants?
While a healthy lifestyle, including a balanced diet and avoiding smoking, is beneficial for general health, there is no conclusive evidence that specific lifestyle changes can prevent the onset of conditions linked to CDH1 variants. It is always best to discuss any concerns with a healthcare provider.
References
- Ghoumid J, Stichelbout M, Jourdain AS. Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1. Genetics in medicine : official journal of the American College of Medical Genetics. 2017. PMID: 28301459
- Hansford S, Kaurah P, Li-Chang H. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA oncology. 2015. PMID: 26182300
- Corso G, Figueiredo J, Biffi R. E-cadherin germline mutation carriers: clinical management and genetic implications. Cancer metastasis reviews. 2014. PMID: 25332147
- Figueiredo J, Söderberg O, Simões-Correia J. The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC. European journal of human genetics : EJHG. 2013. PMID: 22850631
- Oliveira C, Pinheiro H, Figueiredo J. E-cadherin alterations in hereditary disorders with emphasis on hereditary diffuse gastric cancer. Progress in molecular biology and translational science. 2013. PMID: 23481202
- Kobayashi H, Ohno S, Sasaki Y. Hereditary breast and ovarian cancer susceptibility genes (review). Oncology reports. 2013. PMID: 23779253
- Carneiro P, Fernandes MS, Figueiredo J. E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. FEBS letters. 2012. PMID: 22841718
- Fitzgerald RC, Hardwick R, Huntsman D. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. Journal of medical genetics. 2010. PMID: 20591882
- Carneiro F, Oliveira C, Suriano G. Molecular pathology of familial gastric cancer, with an emphasis on hereditary diffuse gastric cancer. Journal of clinical pathology. 2008. PMID: 17513507
- More H, Humar B, Weber W. Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene. Human mutation. 2007. PMID: 17221870
- Park D, Kåresen R, Axcrona U. Expression pattern of adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2007. PMID: 17223851
- Adam MP, Bick S, Mirzaa GM. Diffuse Gastric and Lobular Breast Cancer Syndrome. 1993. PMID: 20301318