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 them invisible when the stomach lining is viewed 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 diffuse gastric cancers 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. In fact, pathologist use the loss of the E-cadherin protein to help 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). However, 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 (the removal of the stomach) is recommended at age 20 to prevent diffuse gastric cancer from occurring. Although you can live without a stomach, 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 to reduce their lifetime risk to <2% (which is significantly lower than the population based risk of 10%). In the absence of surgery, annual breast MRI would be recommended and these would be Medicare funded from age 30.
Does this sound like you or your family? Have you or a relative been diagnosed with diffuse gastric cancer or lobular breast cancer before age 40? Has a CDH1 mutation been detected in a blood relative? Make an appointment with Dr Hilda High at Sydney Cancer Genetics. It is a confidential opportunity to discuss your personal and family history of cancer and genetic testing can be organised, if needed.
These links may be useful
- No Stomach For Cancer is charity based in the USA that provides support for individuals and families affected by gastric cancer, including diffuse gastric cancer.
- The Cancer Genetics section of the Cancer Institute's eviQ website provides up-to-date Australian-based management guidelines
- The US National Library of Medicine website has more information about this syndrome.