Frequently Asked Questions about Hereditary Diffuse Gastric Cancer Syndrome

What is hereditary diffuse gastric cancer syndrome?

Hereditary diffuse gastric cancer (HDGC) syndrome is a condition that makes people more likely to develop a type of stomach (gastric) cancer called diffuse-type and a type of breast cancer called lobular-type.

HDGC is caused by a mutation (change) in the CDH1 gene.

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How is HDGC syndrome diagnosed?

A diagnosis of HDGC syndrome is made with clinical findings (such as the type of cancers you have had), family history, and genetic testing for a mutation in the CDH1 gene.

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What does a positive CDH1 test result mean?

A positive CDH1 test result means that a disease-causing genetic mutation has been found. This means that a person has HDGC syndrome and is at increased risk for developing certain cancers.

The features of HDGC syndrome vary in each person, even among individuals from the same family. It is important to understand that having HDGC syndrome does not mean that a person will definitely develop cancer; it just means that they have an increased risk for developing certain cancers.

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What does a “variant of uncertain significance” (or “ambiguous”) test result mean?

Genes are written in letters called bases. We call the wrong spelling of a gene a “mutation” and a mutation can cause an increased risk of cancer. However, some spelling changes in genes do not cause disease. We are still learning which spellings are normal (harmless) and which may cause disease. Some individuals’ CDH1 gene may be spelled in a way that we can’t say whether it is normal or if it causes disease. These kinds of uncertain changes are called variants of uncertain significance.

If you have a variant of uncertain significance in the CDH1 gene, we may not be able to tell you if it is a normal change or a disease-causing change. In some situations, we may be able to test your relatives for the variant or we may be able to do lab tests, but we still may not be able to tell if the variant will increase your risk for cancer. If you have a variant, we will make cancer screening recommendations based on your family history.

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What does a negative CDH1 test result mean?

A negative test result means that no mutation was found in the CDH1 gene. This could mean any of the following:

  • You could have a mutation in the CDH1 gene that cannot be detected with the testing method that was used. No one genetic testing method can find all mutations.
  • You could have a mutation in a different gene. Your genetic counselor may recommend testing for mutations in other genes that are also associated with stomach cancer, breast cancer, or both.
  • Your personal or family history of HDGC syndrome-like features could be related to other factors such as age, environment, and chance.
  • If your testing was done to look for a mutation that was found in a family member who has HDGC syndrome, then a negative test result for you is considered a “true negative” result. In most cases, this result means that your risk of developing HDGC syndrome-like features (such as cancer) would be the same as the general population.
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How should people with a CDH1 mutation manage their risks for cancers?

The first goal for people with a CDH1 mutation is to prevent cancers. The second goal is to find cancers at early enough stages so they can be treated.

The management of people at risk for gastric cancer is controversial. People who inherit a CDH1 mutation are at a high risk of developing diffuse gastric cancer. Because of this high risk, men and women may consider having a prophylactic (risk-reducing) gastrectomy (removal of the stomach). While this surgery is the best way to prevent cancer for people with a CDH1 mutation, there are risks to consider as well. We also don’t have a lot of information about long-term experience of people who have had a gastrectomy.

In people with CDH1 mutations who do not have a prophylactic gastrectomy, an examination of the stomach, called an upper endoscopy, may be considered. However, this type of screening has not been proven to be helpful or to find cancers at an early stage. As part of the endoscopy, biopsies of areas of concern and random biopsies of the stomach would be performed.

A type of breast cancer known as lobular breast cancer has been reported in families with CDH1 mutations. Women with CDH1 mutations should be screened for breast cancer with mammograms, breast MRI exams, and exams by a doctor starting at age 30 to 35. Women should also be aware of any changes that develop in their breasts.

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If I have a CDH1 mutation, what are the risks to my children?

If you have a CDH1 mutation, each of your children will have a 50% (1 in 2) chance of inheriting the mutation. An individual who inherits the mutation will also inherit the associated risks. It is important to remember that inheriting the mutation does not mean that a person will definitely develop all the features of HDGC syndrome.

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If I have a CDH1 mutation, what are my options for having children?

If you have a CDH1 mutation, you may want to learn about family planning options (starting a family or having more children). For example, embryos can be tested for the family’s genetic mutation before they are even implanted in a woman’s uterus. This process is called preimplantation genetic diagnosis (PGD). PGD is performed with in vitro fertilization (IVF), and may be an option for families who wish to have children without the mutation. To learn more, ask for a referral to a PGD-IVF specialist before attempting pregnancy.

Other possible family planning options include having children with the assistance of donor eggs or donor sperm or through adoption.

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What if I have questions?

If you have any questions or concerns, please contact the MSK Clinical Genetics Service at 646-888-4050.

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