Stomach cancer (hereditary)

Hereditary diffuse gastric cancer is caused by a change to our DNA mutation, our hereditary material. A change to our DNA is called a mutation. Some of these mutations are acquired and others are inherited. Hereditary DNA mutations that can be passed on to our children are also known as germline mutations. DNA mutations can intervene with certain proteins that help our cells (the smallest building blocks of life) operate properly. The CDH1 gene produces a protein we call E-cadherin, which helps cells stick together. A mutation to the CDH1 gene can cause cells to disconnect from one another, which can lead to uncontrollable cell growth. A germline mutation to the CDH1 gene causes diffuse gastric cancer in the lifetime of 60 to 70% of people who inherit the mutation. Sometimes the tumor develops at a young age, but sometimes it develops later in life. Children of parents with a CDH1 mutation have a 50% chance of inheriting this mutation. A woman with this mutation has an additional 40% increased risk of developing breast cancer.

• The genetic screening is discussed in section A below.
• Section B will deal with gastroscopies for people with a proven gene mutation, also in relation to a gastrectomy.
• Section B1 and B2 offer more information about regular stomach and chest screenings.
• Section C lists the examinations proceeding a (preventive) gastrectomy.
• Section D offers advice in case no CDH1 mutation was found but an increased risk of gastric cancer is still suspected.

A. Genetic testing

Please consider seeing your general practitioner if someone in your family developed gastric cancer before they turned 40, or if multiple people in your family developed stomach cancer. If you are over the age of 18 and your doctor thinks it’s necessary, he or she can refer you to the NKI Hereditary tumors Clinic, or consult with one of our gastroenterologists. A clinical geneticist, a physician specialized in genetic and hereditary disorders, and a genetic consultant will take your family medical history and, if your clinical geneticist suspects that you may be a carrier of a gene mutation, he or she can offer you a blood test. The results of this genetic screening could affect the entire family. Our Hereditary Tumors Clinic can provide further information and advice. There are three potential results of genetic screening:

• A person is a carrier of a CDH1 or CTNNA1 mutation which causes an increased risk of illness.
• A CDH1 or CTNNA1 mutation causing an increased risk of illness was found in the family, but the person undergoing the screening is not a carrier.
• No mutation was found in the family, but the family medical history gives reason to believe that the family has an increased risk of developing cancer.

B. Preventive screening for people with CDH1 or CTNNA1 gene mutations

All people with CDH1 mutations are advised to preventively remove the stomach due to their high risk of developing gastric cancer. Some people cannot or will not have their stomach removed (yet) due to their personal circumstances. We recommend that these people come in regularly (usually yearly) for screening through a gastroscopy. The exact risks of developing gastric cancer for people with a CTNNA1 mutation is currently still unclear. People with this gene mutation are currently not advised to have their stomach removed as a preventive measure, but are asked to come in for gastroscopic screening regularly.

Next to these screenings (see paragraph B1), women with CDH1 mutations are also recommended to come in for breast examinations (see paragraph B2). It is currently unknown whether CTNNA1 mutations also increase the risk of developing breast cancer. Some women are regularly screened for breast cancer as part of a trial.

B1. Regular stomach screenings (gastroscopy)

We recommend that people who prefer to come in for regular screenings start at the age of 25. Genetic diffuse stomach cancer before the age of 25 is very rare. Please try and find a physician who has experience in these kinds of screenings. Cancer cells are often small, and their position under the stomach lining makes them easy to miss.
A gastroscopy means that your physician uses a flexible telescope to examine your esophagus and stomach through the mouth. You will be mildly sedated during the procedure, so you will not experience any discomfort. Your doctor will take several stomach biopsies (small ‘bites’ of your stomach lining) which will be further examined by a pathologist.

At the Netherlands Cancer Institute, we screen patients with gene mutations or suspected gene mutations in accordance with the Cambridge protocol. This means that a specifically trained doctor will inspect your stomach through a gastroscopy for about 45 minutes. We use special lighting to gain a better view of any potential abnormalities, and take small biopsies of your stomach lining if anything looks suspicious. We also take approximately 30 biopsies of areas that look normal. Despite these elaborate screenings, we are not always able to detect diffuse stomach cancer. Cancer cells that have spread out throughout the stomach are hard to see and may not be present in the biopsies. Previous pathological (microscopic) research has shown that (superficial) cancer cells were present in preventively removed stomachs of carriers of mutated CDH1 genes, despite their clean screening results.

B2. Regular breast examinations

Women with a CDH1 gene mutation have an increased risk of developing breast cancer of approximately 40%. In order to detect breast cancer earlier, we recommend that these women come in for a yearly screening after the age of 30, and have a mammogram and, if necessary, a breast MRI made. Men with this gene mutation will not receive this same recommendation. It is currently unknown whether CTNNA1 mutations also increase the risk of developing breast cancer. Some women are regularly screened for breast cancer as part of a trial.

C. Tests before (preventive) surgery

If you and your physician have decided to preventively remove the stomach, your physician will want to do one gastroscopic examination and one CT scan of the chest and stomach cavities.

D. No CDH1 or CTNNA1 mutation, but potential increased risk of developing stomach cancer

Not all families in which hereditary diffuse gastric cancer is prevalent, carry the relevant gene mutation. We currently do not know what kind of risk of developing stomach cancer these families have, and cannot tell if close family sees this same risk. We offer a one time or regular stomach cancer screening to the closest family members of patients with hereditary diffuse gastric cancer (brothers, sisters, children).

Treatments for hereditary diffuse gastric cancer can be preventive or therapeutic. Please read more about the various options below.

1A. Preventive stomach removal (prophylactic gastrectomy) for carriers of a CDH1 gene mutation

The prognosis of late-stage diffuse stomach cancer is not good. Through regular stomach cancer screenings, this cancer type can be detected early which offers a better prognosis. Because our examinations have very clear limitations, we currently recommend preventive stomach removal (prophylactic gastrectomy) in the case of CDH1 mutation. During this surgery, the entire stomach will be removed, after which the esophagus and small intestine will be connected. Most people tend to get used to their new lifestyle and meals without a stomach, although the surgery can be drastic and can have radical effects on your quality of life.

You might experience changes to your quality of life due to problems with feeling full, having to eat small amounts throughout the day, heartburn and reflux, fatigue, diarrhea, weight loss, malabsorption (fat, iron, vitamin B12, vitamin D). Many people rely on tube feeding or liquid food for some time after the surgery.

1B. Preventive breast removal (Prophylactic mastectomy) for carriers of a CDH1 gene mutation

Women who carry a CDH1 gene mutation have an increased risk of developing breast cancer. They are advised to come in for a breast screening every year, starting at age 30. Preventive breast removal surgery is not always recommended but can be considered depending on the personal situation.

2. Therapeutic treatment for hereditary diffuse gastric cancer

The only effective treatment for hereditary diffuse gastric cancer is the total removal of the stomach. Diffuse gastric cancer can develop throughout the entire stomach. Through yearly screenings, the tumor cells can be found before they grow too big or spread throughout the layers of the stomach lining, or grow metastatic. The prognosis of early detected tumor cells in the stomach lining is good. If stomach cancer is detected at a later stage (if the cancer cells spread deeper into the lining of the stomach, or if the tumor has spread to the lymph nodes near the tumor), you may need to receive chemotherapy before and after the removal of the stomach. Once the tumor has spread to other organs, the only option is to treat the symptoms and extend the life span. This is called palliative treatment.