Hereditary Diffuse Gastric Cancer syndrome and the CDH1 gene
Hereditary Diffuse Gastric Cancer syndrome is caused by inherited (germline) mutations in the CDH1 gene, and rarely the CTNNA1 gene.
This syndrome is associated with a very high risk of diffuse gastric cancer (up to 80% by age 80) and also lobular breast cancer in women (up to 60% by age 80), with most of the cancers occurring before age 40.
Hereditary Diffuse Gastric Cancer syndrome is very rare, affecting about 1 in 10,000 people. It was first described in 1998 in a New Zealand Maori family
The CDH1 gene encodes the protein E-cadherin. One of E-cadherin’s roles is to help cells stick to one another (cell adhesion) to form tissues and another is control cell grow and division.
Diffuse gastric cancer is a rare type of stomach cancer. It is also referred to as signet ring carcinoma because of how the cells look under the microscope. The cancers tend to grow just beneath the stomach lining, making the invisible when the stomach lining is view via a gastroscopy. Also, because the E-cadherin protein isn't working, the cells grow in single rows rather than lumps and are more likely to break off and spread (metastasise).
Of the 2000 to 2500 new gastric cancers diagnosed each year in Australia, only a small amount are diffuse gastric cancers. However, more than 1 in 3 of these will be due to an inherited CDH1 gene mutation
CDH1 mutations are also associated with breast cancer of the lobular type. Both copies of the E-cadherin gene are damaged in lobular breast cancers (staining for to demonstrate loss of the E-cadherin protein as well as the protein made by the CTNNA1 gene b catenin, is one of the main ways pathologist differentiate lobular breast cancers from the more common ductal kind.). In most lobular breast cancers the CDH1 genes were damaged as the cancer grew (somatic mutations).
A woman who has inherited a CDH1 mutation (a germline mutation) is at very high risk of lobular breast cancer. This risk starts to rise at age 30, with a lifetime risk of 30 to 60%.
Management of Hereditary Diffuse Gastric Cancer syndrome
Because the gastric and breast cancers that occur do not form lumps, they can be very difficult to detected and may spread very early.
Gastrectomy is recommended at age 20 and is curative. Even though diffuse gastric cancers have been detected in children, this is rare. You can live without a stomach. However, there is usually quite significant weight loss in the first 6 months following gastrectomy. That's why gastrectomy is not recommended in children: you need to balance the small risk against the need for growth and development.
Gastrectomy is the only truly effective way to remove the risk. For individuals who don't want to pursue gastrectomy unless a cancer was detected, endoscopic surveillance in expert centres and involving multiple biopsies is recommended. Gastrectomy over age 70 is not recommended.Some women who carry a CDH1 mutation elect to pursue bilateral risk reducing mastectomies (RRM) to reduce their lifetime risk to <2% (which is significantly lower than the population based risk of 10%). We reviewed that Kelsey’s risk at her current age is small. While Kelsey does not need to wait until age 30 if she is keen to pursue mastectomies, it would be important to know that she has recovered from and adapted to her gastrectomy before undertaking further surgery. In the absence of surgery, annual breast MRI would be recommended and these would be Medicare funded from age 30. I stated that there is a 50% chance of a person who carries a CDH1 mutation, whether male or female, passing the mutation to their son or daughter. We reviewed that preimplantation genetic diagnosis (PGD) in the setting of in vitro fertilisation (IVF) can be used prevent the familial mutation being passed on to future offspring. This does not increase risk of cancer for the mother nor increase risk of congenital problems to a baby.