Abnormal growth of the cell leading to the formation of a cell that forms a tumour and may or may not be malignant. It is supposed that cancer was a genetic disorder but some researchers are saying that it is a mitochondrial disorder. Because most of the energy that is ATP is provided by the mitochondria and oxidative phosphorylation which occur in a normal cell does not occur in some cancer cells. Hereditary diffuse gastric cancer (HDGC) is a rare inherited condition associated with an increased risk of gastric (stomach) cancer.
Types of cancer
Carcinoma – They are the most common type of cancer. They are formed by epithelial cells which cover the inside and outside surfaces of the body.
Adenocarcinoma – Cancer that forms in epithelial cells that produce fluids or mucus.
Squamous cell carcinoma– Cancer that forms in squamous cells, which are epithelial cells that lie beneath the outer surface of the skin.
Sarcoma – Cancers that form in bone and soft tissues including blood vessels and tendon and ligaments.
Leukaemia – Cancers that begin in the blood-forming tissue of the body that is bone marrow.
Lymphoma – Cancer that begins in lymphocytes.
And there are many more cancers like melanoma that begin in melanocytes, brain and spinal cord tumours.
What is Hereditary Diffuse Gastric Cancer?
Our Stomach plays a very important role in the digestion of food. It is associated with mixing of the food and releasing of certain gastric juices and breakdown of the food.
The food is then passed to the small intestine for further breakdown.
Types of stomach cancer
Usually, there are two types of stomach cancer
The first one is intestinal-type adenocarcinoma which is caused due to infection with Helicobacter pylori, the cause is alcohol consumption and smoking.
Diffuse gastric cancer (DGC) also known as signet ring carcinoma.
A small number of people who have diffuse gastric cancer are associated with HDGC hereditary gastric cancer syndrome it is due to heterozygous germline mutation in the E-cadherin (CDH1 gene).The word used for diffusion because cancer tends to diffuse in the entire stomach. 20 per cent of stomach cancer are diffuse gastric cancer and a small amount of them due to HDGC.
Hereditary diffuse gastric cancer (HDGC) is a rare inherited condition associated with an increased risk of gastric (stomach) cancer.
The average age for someone with HDGC to be diagnosed with gastric cancer is 38 yrs.
Women who have HDGC has a high risk of breast cancer.
What causes HDGC?
HDGC is an inherited genetic disorder that is very rare.
This means that it can be passed from one generation to another.
Gene which is associated with HDHC is called CDH1.
Mutation in this CDH1 gene leads to the development of gastric cancer and breast cancer which are associated with the ADHC.
Another gene that could be associated with HDGC is CTNNA1.
E- Cadherin And Relation With The CDH1
CDH1 gene is a tumour suppressor gene and located on chromosome 16q. This transcribe protein is called E-cadherin. E-cadherin belong to the family of a transmembrane glycoprotein called cadherin. Cadherin main function is to attach one cell to another that is maintain cell adhesion to form organized tissues. They are attached to the cytosolic domain to the extracellular calcium dependant domain. These structures provide cell stability and they inhibit cell motility also.
How Is HDGC Inherited?
CHD1 is a tumour suppressor gene and both alleles have to be silenced for loss of protein.
A second hit is required for inactivation of the gene which can be due to methylation of CDH1 gene causing mutation and loss of heterozygosity.
We know that every cell has 2 copies of each gene. One which comes from the father and another one from the mother.
HDGC follow an autosomal dominant inheritance pattern which means a mutation will happen in only one copy of the gene. So it means it is transmitted from the parent to the offspring, with the normal gene the mutated gene is also passed. This is also known as a germline mutation.
When the parent carrying the mutated gene wants to have a baby they are recommended to go through PGD (preimplantation genetic disorders).In this process, a women’s egg is removed and fertilized and when it becomes an embryo, one cell is removed and tested for hereditary disorders.
E-Cadherin and Signalling Pathways in Cancer
The exact mechanism of CDH1 mutations in carcinogenesis continues to be investigated. The role of E‐cadherin is mainly cell adhesion and complex function in β-catenin and other signalling pathways.
CDH1 gene mutation and the associated protein which is E-cadherin lead to epithelial-mesenchymal transition.
Other important pathways which are RTK and MAPK pathway are associated with this e- cadherin.
The altered gene of e cadherin leads to loss of cell adhesion and disruption of a specific pathway which altered cell migration and thus promotes tumorigenesis.
E –Cadherin and other pathways associated with it
WNT -1 pathway
E cadherin bind to the β-catenin, this bind directly to distal region α-catenin which is coupled to cadherin.
E-cad protein is lost, there is excess un-sequestered cytoplasmic β-catenin that escapes degradation and enters the nucleus to bind to TCF and activate the Wnt pathway.
The Wnt pathway is involved in the development of benign and malignant tumour.
Snail and Zeb-1 pathway
E cadherin plays an important role in EMT transition by suppressing the snail and Zeb-1 transcription factor.
A loss in e cadherin or disruption leads to promotion of epithelial cell to mesenchymal which means the cell structure is disrupted and this lead to metastatic disease.
E-cadherin and its associated signalling pathways play an important physiological role in maintaining cell-cell adhesions, architecture, motility, role in cell signalling pathways and cell homeostasis.
Any mutation in the E- cadherin gene may lead to mutation of the CDH1 gene which leads to gastric carcinogenesis.
However, only about 20% to 30% of families that appear to have HDGC will have a mutation found in the CDH1 gene.
And early detection of the CDH1 gene mutation can lead to reducing the risk and selecting appropriate therapy for the patient.