Stomach cancer (hereditary)

The Netherlands Cancer Institute (NKI) is an NFU certified expert center for hereditary stomach cancer, also known as gastric cancer. The NKI treats the most patients with hereditary stomach cancer in the country and its hereditary gastric cancer team is part of the “International Gastric Cancer Linkage Consortium”, an organization that creates international guidelines for treatment for people with hereditary stomach cancer.

The NKI is a Comprehensive Cancer Center, which means that our institute meets the highest quality standards in research and care. We distinguish ourselves through a fully integrated cooperation between research and care, which is reflected in the close collaboration between researchers and clinicians in our NKI hereditary stomach cancer team.

What is hereditary stomach cancer?

Approximately 1700 people are diagnosed with stomach cancer every year in the Netherlands. There are two main types of stomach cancer:

  1. Diffuse gastric cancer
  2. Intestinal gastric cancer

Some stomach tumors show characteristics of both types. We call these tumor types mixed.

The word diffuse refers to the way this tumor grows by infiltrating the surrounding tissue. It is therefore harder to differentiate between tumor cells and regular cells in the stomach lining.
The intestinal type of stomach cancer is easier to distinguish. Approximately 4% of people with diffuse gastric cancer developed a tumor due to a hereditary risk.
If diffuse gastric cancer, or breast cancer, occurs in the family, or if diffuse gastric cancer occurs at a young age, you may want to consider genetic tests to see whether you inherited a higher risk of these cancer types.

The process during which people decide to get tested for genetic abnormalities – or face follow-up examinations or even intensive surgeries with long-lasting effects – can be highly emotionally taxing. People often experience mixed feelings, as well as uncertainties, as there are still many things we don’t know about hereditary diffuse gastric cancer. We recommend seeking out a specialized center that offers care from multidisciplinary teams for your guidance, examinations and tests, treatment, and follow-up care.

Physical symptoms of (hereditary) diffuse gastric cancer

Stomach cancer initially does not cause symptoms. Only once the tumor cells have spread through the stomach lining will symptoms arise. Possible symptoms you might experience are:

  • Loss of appetite.
  • Weight loss without a cause.
  • A feeling of fullness after a small meal.
  • Pain in the upper abdomen and/or near the sternum
  • Nausea.
  • Regular vomiting or vomiting up (small bits of) blood.
  • Dizziness and fatigue from anemia caused by long-term blood loss from the stomach.

Causes of hereditary diffuse gastric cancer

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.

CDH1 gene and new mutation

A CDH1 gene mutation is found in less than a third of families in which more than one member developed diffuse gastric cancer, or in which a member developed this tumor type at an early age. Other families may still have a hereditary risk, but we aren’t sure yet what DNA mutation could be the cause of this. Despite not knowing their risk of developing stomach cancer, we recommend that all members of these families come in for regular screenings.

The Netherlands Cancer Institute recently discovered a new mutation in a family facing many instances of diffuse gastric cancer. These family members all had a mutation to the CTNNA1, which regulates the production of the alpha-catenin protein, which also helps cells stick together. We currently don’t know enough about the consequences of such a CTNNA1 gene mutation, which will have to be discovered through research.

Options for people with a potential genetic risk factor

People who may have inherited a higher risk for stomach cancer often face hard decisions. The two main decisions are whether or not to do genetic testing, and whether to remove the stomach as a preventive measure (gastrectomy) if it turns out that he or she carries this gene mutation.

Our hereditary stomach cancer team has expertise and experience in order to inform you about your options and any relevant considerations. Our experience has shown that such an information session can help to reach a well-informed decision. Next to surgical, technical, and endoscopic expertise, our team has plenty of time for your questions and potential nutritional problems that may arise after surgery. Some questions you may have are:

  • What are the pros and cons of genetic testing?
  • How should you deal with an increased risk of stomach cancer?
  • What kind of practical concerns should you take into account once a gene mutation has been discovered? Think, for example, of life insurance policies, mortgages, loans, or jobs.
  • How to deal with family-related concerns or problems within the family about a possible familial or hereditary increased risk of stomach cancer, and your sense of responsibility towards your other family members.
  • What are the results of hereditary increased risk on child-related matters? Consider care for children with an increased risk or fear of having to leave children behind.
  • What are the pros and cons of preventive stomach removal (gastrectomy)?
  • When is the ideal time for such a radical surgery?
  • Are there any challenges related to pregnancy after a gastrectomy?
  • How to deal with family members who have developed cancer, or your own, or the feat of developing cancer or losing family members to the illness.
  • How do other people deal with emotions like anger, fear, loss, relief, and uncertainty?
  • How to deal with nutrition after gastrectomy, and how to gain weight.
  • How to pick your life back up after a preventive gastrectomy, in terms of day to day activities, nutrition, family life, social life, physical activity, and work.

Diagnostics and prevention hereditary diffuse gastric 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

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.