The CDH1 gene provides the genetic code for producing epithelial cadherin, a protein critical for cell adhesion, tumor suppression, and several other functions.
Epithelial cadherin, also called E-cadherin, is a protein found in epithelial cells. Specifically, e-cadherin is in the exterior wall of epithelial cells. Epithelial cells are found in the lining of our body cavities. For instance, our mouth and eyelids. The National Institutes of Health says that e-cadherin: “is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body, such as the inside of the eyelids and mouth.”
According to the National Institutes of Health, relatively speaking, we know a lot about the E-cadherin protein: “E-cadherin is one of the best-understood cadherin proteins.” We know that E-cadherin has multiple functions. First, it helps neighboring cells stick to each other. This is called cell adhesion. Because the cells are able to stick to one another, the cells are able to form tissue. In the words of the National Institutes of Health: “E-cadherin belongs to a family of proteins called cadherins whose function is to help neighboring cells stick to one another (cell adhesion) to form organized tissues.”
Second, E-cadherin helps suppress tumors. The National Institutes of Health says: “E-cadherin also acts as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.” Similarly, a paper published in the British Journal of Cancer explains that CDH1’s role in cell adhesion makes it critical for preventing tumor cell invasion of neighboring tissue: “CDH1 is mainly responsible for adherence junctions between epithelial cells (Tsanou et al, 2008) and therefore implicated in the progression of tumour invasion (Chen et al, 2012; Lu et al, 2012). “
Third, E-cadherin participates in transmitting chemical signals inside cells. Fourth, it helps control maturing cells. Fifth, it is involved in cell movement. Sixth, it participates in regulating the activity of some genes. For instance, it interacts with certain other proteins that are considered important for head and face development. See the National Institutes of Health.
For E-cadherin to function properly in these many roles, the CDH1 gene must provide the proper instructions. With the proper instructions, the E-cadherin protein is exactly what the human body expects it to be. For instance, it is the expected length, folds into its expected formation, and has all expected functioning parts. This ensures that it can interact with cells, other proteins, and the human body in its expected ways.
However, if the CDH1 gene provides improper instructions for making E-cadherin, it can result in an E-cadherin protein that is incapable of serving its required roles. When a gene provides improper instructions, it is because the gene is mutated. For instance, a mutated gene may be missing critical instructions, have additional instructions that should not be there, or have some of its instructions jumbled in the wrong order.
Such mutations can cause the resulting protein to not resemble the protein that was expected to be produced by the genetic instructions. For instance, the protein made from a mutated gene may not be long enough, it may not fold into the proper formation, or it may be missing key parts required for performance. Essentially, in at least one critical way, the resulting E-cadherin protein produced by a mutated CDH1 gene may not resemble the E-cadherin protein produced by a non-mutated CDH1 gene.
When an E-cadherin protein does not resemble its expected form, it may not function properly. For instance, one hypothetical example, if the E-cadherin protein is missing an exon, the protein may not fold in the correct formation. Accordingly, when it encounters a protein that is supposed to receive it, the mutated E-cadherin may not fit into its receptor. Like a key and lock, the lock does not recognize the key. Hence, the expected result of the two proteins coming together (for instance, a critical step in the cell-adhesion process) will not be triggered because the E-cadherin protein is incapable of triggering the expected event. That is just one hypothetical, oversimplified example.
Different mutations may cause different results in patients. For instance, here is an excerpt from a 1999 paper published by European researchers: “Interestingly, there is a major difference in mutation type between diffuse gastric and infiltrative lobular breast cancers. In diffuse gastric tumors, the predominant defects are exon skippings, which cause in‐frame deletions. By contrast, most mutations found in infiltrating lobular breast cancers are out‐of‐frame mutations, which are predicted to yield secreted truncated E‐cadherin fragments.”
As explained more fully below, having cells with only one mutated CDH1 gene is not itself the entirety of the problem. All of your cells have two copies of the CDH1 gene. You inherit one from your mom and the other from your dad. If neither have a mutation, you will have properly functioning E-cadherin proteins. Hence, no resulting gastric or breast cancer.
Though not everyone is born with two good CDH1 genes. CDH1 mutation carriers oftentimes inherit a mutated CDH1 gene from one of their parents. In such cases, instead of inheriting good CDH1 genes from both parents, CDH1 mutation carriers may get a good copy from one parent and a mutated copy from the other. This means they have only one good CDH1 gene.
Despite the mutation, CDH1 mutation carriers appear to not develop CDH1-mutation-related diseases unless their good CDH1 gene suffers a mutation. Researchers began reporting this in 1999 and 2000.
Shortly before then, in the late 1990s, researchers discovered a connection between CDH1 mutations and cancer, specifically diffuse gastric cancer and lobular breast cancer. For instance, in 1998, Dr. Parry Guilford and his colleagues published a paper that reported, for the first time ever, a connection between CDH1 gene mutations and gastric cancer. They wrote: “The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families.” Their publication concludes: “These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.”
Following their 1998 paper, in 1999, Dr. Guilford and his colleagues published another paper. This time, they expanded their research to include five additional families having a history of diffuse gastric cancer and breast cancer. The authors write: “Heterozygous inactivating mutations were found in the E‐cadherin gene in each of these families.”
According to the authors, CDH1 gene mutations cause diffuse gastric cancer and potentially breast cancer. The authors wrote: “These results demonstrate that germline mutation of the E‐cadherin gene is a common cause of hereditary diffuse gastric cancer and suggest a role for these mutations in the incidence of breast cancer.”
Not only were Dr. Guilford and his colleagues making these conclusions. Others agreed. For instance, in 1999, European researchers observed a connection between CDH1 gene mutations and gastric and breast cancers. They wrote: “Frequent inactivating mutations have been identified for the E‐cadherin gene (CDH1) in diffuse gastric cancers and lobular breast cancers. To date, 69 somatic mutations have been reported comprising, in addition to few missense mutations, mainly splice site mutations and truncation mutations caused by insertions, deletions, and nonsense mutations.”
In 2000, Dr. Guilford and his colleagues published an important finding for understanding how CDH1 mutations impact its carrier. Specifically, they concluded that CDH1 mutation carriers do not develop gastric or lobular breast cancer until both CDH1 genes are mutated. The authors concluded: “These findings suggested the hypothesis that CDH1 promoter methylation might function as the ‘second genetic hit’ in the genesis of these cancers.” In other words, this “second hit” is required for CDH1 gene mutation carriers for developing gastric or breast cancer.
Dr. Guildford’s paper builds on an earlier-publish statement made by European researchers. Those researchers said that in most cases of CDH1 gene mutations resulting in gastric or breast cancer, the good copy of the CDH1 gene had mutated too. They wrote: “In most cases, these mutations do occur in combination with loss of heterozygosity (LOH) of the wild‐type allele.”
Watch the Keynote Speaker at the 2018 ESMO World Congress on Gastrointestinal Cancer. She presented on hereditary aspects of gastric cancer and, in the process, talks about the CDH1 gene.