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Stomach cancer (hereditary)

The Netherlands Cancer Institute (NKI) is an NFU certified expertise center for hereditary stomach cancer. The NKI sees the most patients in the Netherlands with a hereditary predisposition to stomach cancer. The hereditary gastric cancer team from the NKI is part of the "International Gastric Cancer Linkage Consortium" that draws up the international guidelines for people with hereditary gastric cancer.

The NKI is also a 'Comprehensive Cancer Center', which means that it meets the highest quality requirements for research and care. Typically, research and care are closely linked. This connection is also reflected in the Hereditary Stomach Cancer team of the NKI, in which researchers and healthcare providers work together intensively.

What is hereditary stomach cancer?

The diagnosis of stomach cancer is made in about 1700 people in the Netherlands every year. Roughly speaking, there are two different types of stomach cancer:

  1. The diffuse type of stomach cancer
  2. the intestinal type of stomach cancer

A stomach tumor can also have characteristics of both types, we speak of the mixed type.

The word 'diffuse' refers to the growth habit of this type of stomach cancer, in which the tumor sprouts swispy and the individual tumor cells are often difficult to demarcate from the normal gastric mucosa.
The intestinal type of stomach cancer is better separated from normal gastric mucosa. In about 4% of all patients with diffuse type of stomach cancer, hereditary predisposition plays a role.
If diffuse stomach cancer, and sometimes breast cancer, often runs in the family, or if diffuse stomach cancer occurs at a young age, there may be reason to test for a hereditary predisposition by doing a genetic (heredity) test.

The process in which people decide to get tested for genetic abnormalities, have follow-up tests carried out or undergo operations with sometimes far-reaching consequences is often complicated and emotionally taxing. Conflicting feelings and uncertainties play a role in this. For this reason and because there is still a lot of uncertainty about hereditary diffuse stomach cancer, it is recommended that the guidance, examinations, treatments and aftercare take place by a multidisciplinary team in a specialized center.

Physical symptoms of (hereditary) diffuse stomach cancer

In the early stages, stomach cancer does not cause any symptoms. Only when tumor cells have spread extensively through the stomach wall can complaints arise. Possible complaints are:

  • Decreased appetite.
  • Unexplained weight loss.
  • Feeling full quickly after eating.
  • Pain in the upper abdomen and/or near the sternum.
  • Nausea.
  • Frequent vomiting or vomiting of (small amounts of) blood.
  • Dizziness and fatigue due to anemia with prolonged blood loss from the stomach.

Causes of hereditary diffuse stomach cancer

Hereditary diffuse stomach cancer is caused by DNA change. DNA is our genetic material. A change in the DNA is called a mutation. Some DNA changes are acquired and some DNA changes are innate. DNA changes that are congenital and that can be passed on to children are called a germline mutation. Changes in DNA can cause certain proteins responsible for the functioning of cells (the smallest building blocks that make up our body) to stop working properly. The CDH1 gene is responsible for the production of a protein called E-cadherin. This protein ensures that cells stay together. A mutation in the CDH1 gene can cause this protein to not work properly and that the cells therefore easily lose contact with each other. This can cause uninhibited growth of cells. A germline mutation in the CDH1 gene causes diffuse stomach cancer in 60-70% of people during life. This can take place at a young age, but also at a later age. Children of a parent with a CDH1 mutation have a 50% chance of inheriting this mutation from their parent. A woman with this mutation also has a 40% increased risk of developing breast cancer during her lifetime.

CDH1 gene and new mutation

In less than one third of the families (in which diffuse type of stomach cancer and/or at a young age diffuse type of stomach cancer occur in several people), a mutation in the CDH1 gene is found. In the other families, there may be a hereditary predisposition, but it is not known which part of the DNA is responsible for this. Although the risk of developing stomach cancer is unclear for these people, these family members are often advised to have their stomach examined regularly by means of an exploratory examination.

Recently, the Netherlands Cancer Institute discovered a new mutation in a family in which the diffuse type of stomach cancer was common. This is a mutation in the CTNNA1 gene. The CTNNA1 gene is responsible for the production of the alpha-catenin protein, which is also a protein that normally ensures that the cells stay together. At the moment, little is known about the consequences of having a mutation in the CTNNA1 gene. Further research is being done on this.

Options for possible hereditary predisposition

People with a possible hereditary predisposition to stomach cancer face various often difficult choices. Two important choices are: whether or not to have genetic testing done; whether or not to undergo a preventive gastric removal if it turns out that someone is a carrier of a CDH1 gene mutation.

The Hereditary Stomach Cancer Team has specific knowledge and experience and can provide good information about the options and considerations that can have an influence. Experience shows that this makes it easier to make informed decisions. In addition to surgical, technical and endoscopic expertise, the team also pays extensive attention to questions and any nutritional problems that may arise after surgery. Specific questions may include:

  • What are the advantages and disadvantages of genetic testing?
  • How do you deal with an increased risk of cancer?
  • What should you look for in practical matters such as obtaining life insurance, a mortgage, loans or a job if it is discovered that you have a gene mutation?
  • How do you deal with family-related matters such as communication (problems) within the family about a possible familial or hereditary predisposition to stomach cancer and the sense of responsibility towards other family members?
  • What are the consequences of a hereditary predisposition on child-related issues such as worries about children who have an increased risk, fear of having to leave children behind?
  • What are the pros and cons of preventive stomach removal?
  • What is the best timing of such a major operation?
  • What are the experiences with getting pregnant and pregnancy after a stomach removal?
  • How do you deal with cancer in family members or yourself? How do you deal with the fear of getting cancer and the grief of losing family members to cancer?
  • What are the experiences with emotions such as fear, anger, feelings of loss, feelings of relief and insecurity?
  • How do you deal with nutrition after a gastric removal? How can you gain weight?
  • How do you pick up where you left off after a preventive stomach removal in terms of daily rhythm, diet, family life, social life, sports and work?

Diagnosis and prevention of hereditary diffuse stomach cancer

  • In part A below, the genetic test is discussed.
  • In part B, gastric examination (gastroscopy) in people with a proven gene mutation is discussed, also in relation to gastric surgery.
  • In parts B1 and B2 you will find more information about the regular stomach and breast examinations.
  • Part C lists the examinations prior to (preventive) surgery.
  • Part D discusses what the advice is if no CDH1 mutation is found, but there may be an increased risk of stomach cancer.

A. Genetic testing

If someone in the family has developed stomach cancer before the age of 40 or if several people in the family have had stomach cancer, it is advisable to discuss this with your doctor. If necessary, the general practitioner (from the age of 18) can refer to the Clinical Genetics, formerly the Familial Tumors Outpatient Clinic, of the Netherlands Cancer Institute or consult with one of our MDL doctors. A clinical geneticist, a doctor who specializes in heredity and hereditary disorders, and a genetic counselor will go through the family's medical history in detail. If the clinical geneticist considers an increased risk of being a carrier of a hereditary change (gene mutation) possible, genetic testing can be offered via a blood test. The results of genetic testing can have consequences not only for the person seeking advice but also for family members. The Family Tumors Outpatient Clinic provides more information and advice about this. There are three possible results of genetic testing:

  • someone can be a carrier of a disease-causing CDH1 or CTNNA1 mutation.
  • a disease-causing CDH1 or CTNNA1 mutation has been found in the family, but the person tested does not appear to be a carrier of the mutation.
  • No mutation has been found in the family, but based on the family history there may be an increased risk.

B. Preventive examination in case of a demonstrated CDH1 or CTNNA1 gene mutation

In principle, people with a CDH1 mutation are advised to have the stomach removed as a precaution (preventively), because of the high risk of getting stomach cancer. Individual circumstances may mean that people are unwilling or unable to undergo preventive surgery (yet). Then it is recommended to have the stomach checked regularly (usually annually) by means of an exploratory examination (gastroscopy). The exact risk of getting stomach cancer with a CTNNA1 mutation is not yet clear. For the time being, people with this mutation are not routinely advised to have their stomach removed as a precaution, but in particular to have regular gastroscopic examinations performed.

In addition to stomach examination (see also paragraph B1), breast examination (see also paragraph B2) is also recommended for women with a CDH1 mutation. It is unknown whether a CTNNA1 mutation also increases the risk of developing breast cancer. In a research context, breast examination is offered to the group of women with this mutation.

B1. Regular stomach examination (gastroscopy)
If you opt for regular stomach examinations, it is advised to start from the age of about 25. Hereditary diffuse stomach cancer before the age of 25 is rare. It is important to have the stomach examination performed by a doctor who has specific experience with this. Because the areas with cancer cells are often small and lie under the gastric mucosa, they can easily be overlooked.
During a gastroscopy, the doctor uses a flexible tube to look into the stomach through your mouth and esophagus. This is done under a light anaesthetic, so that you do not notice anything of the examination. During this examination, biopsies (small bites of the gastric mucosa) are taken from the stomach and examined under the microscope by a pathologist.
At the Netherlands Cancer Institute, this research is done on people with a gene mutation or suspected gene mutation, according to the so-called 'Cambridge protocol'. This involves a specifically trained doctor doing an extensive gastroscopy of about 45 minutes. Special light is used to better visualize any deviations. Biopsies are taken from mucous membrane which looks abnormal. Furthermore, more than 30 biopsies are often taken, spread over the stomach surface which looks normal. Even this examination is not always sufficient to detect diffuse stomach cancer. Cancer cells that have spread throughout the stomach can be difficult to see and missed when taking biopsies. Previous pathological (microscopic) examination has shown that there were still (superficial) cancer cells in preventively removed stomachs of CDH1 mutation carriers, while the stomach examination had not yielded any abnormalities.

B2. Regular breast examinations

Women who have been shown to have a CDH1 gene mutation have a risk of about 40% of developing breast cancer. To detect breast cancer in women early, annual breast examination from the age of 30 is recommended. In addition to physical examination, a mammogram and possibly an MRI of the breasts are made. This advice does not apply to men. It is not known whether a CTNNA1 mutation also increases the risk of developing breast cancer. However, breast screening is offered to the group of women with this mutation in a research context.

C. Examinations prior to (preventive) surgery

If it is decided together with you to remove the stomach as a precaution, a one-time gastroscopy and a CT scan of the chest and abdominal cavity will be made before the operation.

D. No CDH1 or CTNNA1 mutation, but possibly an increased risk of gastric cancer

By no means all families that meet the standards for hereditary diffuse stomach cancer have a disease-causing mutation. It is not known how high the risk of stomach cancer is in these families, nor is it known which of the closest relatives have an increased risk of stomach cancer. We offer close relatives (brothers, sisters, children) of a patient with familial diffuse stomach cancer a one-off or regular stomach examinations if necessary.

Treatment for hereditary diffuse stomach cancer

Treatments for hereditary diffuse stomach cancer can be preventive or therapeutic. Read below what the different options can be.

1A. Preventive removal of the stomach (total gastric resection) in CDH1 mutation carriers

The prognosis of an advanced stage of diffuse stomach cancer is poor. It seems that regular stomach examinations can detect stomach cancer at an early stage, making the prognosis more favorable. Because the studies also have clear limitations, the current advice is to have the stomach removed as a precaution (preventive total gastric resection) if there is a CDH1 mutation. In a preventive total surgery, the entire stomach is removed and a new connection is made between the esophagus and the small intestine. As a result, the risk of getting stomach cancer has disappeared. Although most people get used to the changing lifenostyle and eating without a stomach fairly quickly, many people experience the operation as drastic with lasting consequences for the quality of life.

The quality of life can decrease because people suffer from symptoms such as: feeling full quickly, often having to eat small amounts, regurgitation of food and bile in the throat, fatigue, attacks of diarrhea, weight loss, less absorption of fat, iron, vitamin B12, and vitamin D. Many people use tube feeding or drinking food for a long period of time after surgery.

1B. Preventive removal of the breasts (breast amputation on both sides) in CDH1 mutation

Women with a CDH1 mutation also have an increased risk of developing breast cancer. The advice to them is to have their breasts examined extensively every year from the age of 30. A preventive removal of the breasts is not recommended as standard, but can be considered in individual cases.

2. Therapeutic treatment if hereditary diffuse stomach cancer has been discovered

Removing the entire stomach is the only effective way to treat hereditary diffuse stomach cancer. Diffuse stomach cancer can occur in all places in the stomach. If stomach examinations are done annually, the groups of tumor cells that are found are often still small, they do not yet grow through the wall layers and do not yet metastasize. The prognosis for discovering such small groups of tumor cells in the gastric mucosa is good. If stomach cancer is detected at a more advanced stage (for example, if the cancer cells have spread deeper into the wall layers of the stomach or if lymph node metastases have developed near the tumor), chemotherapy before and after a stomach removal may be advised. When metastases are found in other organs, healing is no longer possible. In that case, the doctor can suggest various treatments to reduce the symptoms and extend your lifespan. This is called palliative treatment.

The treatment team

Surgeons

Gastroenterologists

Pathologists

Specialists in supportive care and rehabilitation

Specialists Familial Tumor Outpatient Clinic

Nurse specialists

Disclaimer

This translation was generated automatically based on information in Dutch. It has not been reviewed by a medical specialist. The purpose of this translation is to make our information accessible to non-Dutch speakers. However, this information should not be considered a substitute for medical advice from your treating physician. The Netherlands Cancer Institute cannot guarantee the accuracy of this translation. For medical questions or advice, please consult your physician.

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