Hereditary diffuse gastric cancer (HDGC) is an inherited disorder that greatly increases the chance of developing a form of stomach(gastric) cancer. In this form, known as diffuse gastric cancer, there is no solid tumor. Instead cancerous (malignant) cells multiply underneath the stomach lining, making the lining thick and rigid. The invasive nature of this type of cancer makes it highly likely that these cancer cells will spread (metastasize) to other tissues, such as the liver or nearby bones.

Symptoms of diffuse gastric cancer occur late in the disease and can include stomach pain, nausea, vomiting, difficulty swallowing (dysphagia), decreased appetite, and weight loss. If the cancer metastasizes to other tissues, it may lead to an enlarged liver, yellowing of the eyes and skin (jaundice), an abnormal buildup of fluid in the abdominal cavity (ascites), firm lumps under the skin, or broken bones.

In HDGC, gastric cancer usually occurs in a person's late thirties or early forties, although it can develop anytime during adulthood. If diffuse gastric cancer is detected early, the survival rate is high; however, because this type of cancer is hidden underneath the stomach lining, it is usually not diagnosed until the cancer has become widely invasive. At that stage of the disease, the survival rate is approximately 20 percent.

Some people with HDGC have an increased risk of developing other types of cancer, such as a form of breast cancer in women that begins in the milk-producing glands (lobular breast cancer); prostate cancer; and cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. Most people with HDGC have family members who have had one of the types of cancer associated with HDGC. In some families, all the affected members have diffuse gastric cancer. In other families, some affected members have diffuse gastric cancer and others have another associated form of cancer, such as lobular breast cancer. Frequently, HDGC-related cancers develop in individuals before the age of 50.

Hereditary Diffuse Gastric Cancer (HDGC) is a rare cancer syndrome that leads to a higher-than-average risk of developing two types of cancer: diffuse gastric cancer (DGC) and lobular breast cancer (LBC). The word “hereditary” means that the syndrome is passed down from a parent to their child.

Diffuse gastric cancer is a type of cancer that grows and spreads within the lining of the stomach. Because it does not typically cause a bulky tumor to develop, it is more difficult to find and more likely to be found at a later stage when it can be very difficult to treat successfully.

How does a person get HDGC?

HDGC is inherited, meaning the syndrome (a set of symptoms or signs that occur together and suggest the presence of a disease or increased chance of developing a disease) is passed down from a parent to a child. Most families with HDGC have a mutation (a change in the genetic code) in a gene called CDH1. When it functions correctly, CDH1 acts as a tumor suppressor, preventing cancers from growing. However, mutations in CDH1 could possibly lead to the development of cancer. Mutations in a gene that contribute to the development of a disease are known as pathogenic variants.

Everyone has two copies of the CDH1 gene, one from their mother and one from their father. Because of the nature of CDH1, you only need one of your two copies to have a pathogenic variant to be affected by HDGC. When you have a parent with HDGC caused by a pathogenic variant in the CDH1 gene, you have a 50 percent chance of also having that same mutation.

In a small number of cases, HDGC is caused by a mutation in a different gene called CTNNA1. This gene functions similarly to CDH1.

HDGC is diagnosed when a person or family tests positive for a pathogenic variant in the CDH1 or, more rarely, the CTNNA1 gene.

What should I do if I suspect my family has HDGC?

It is important to learn about the health of your family members, especially any diagnosis of cancer. If you can, try to gather information on the types of cancer your family has experienced, pathology reports from doctors, the age of the family member at diagnosis and, if it applies, the age that they died.

Tell this information to your primary care provider. If you think your family might have HDGC syndrome, you can request a referral to a genetic counselor to discuss this and consider genetic testing.

What does it mean to have HDGC?

If you are diagnosed with HDGC syndrome, it does not necessarily mean that you have or will develop cancer — you just have a higher risk. People with HDGC may develop none, one or more than one cancer. Being diagnosed with one type of cancer does not mean that the risks for other cancers no longer apply.

Though it can be difficult to estimate your exact risk of cancer:

• Some studies show that individuals with a pathogenic CDH1 gene variant and a strong family history of stomach cancer have up to a 70 percent risk of having diffuse gastric cancer in their lifetime; however, it is generally accepted that the risk is in the 30 to 40 percent range.
• Women with HDGC have an estimated 40 to 55 percent risk of having lobular breast cancer in their lifetime.
• People with HDGC and little or no family history of stomach cancer may have a lower risk of diffuse gastric cancer, but family history may not be a completely reliable factor in determining cancer risk.

These cancers can affect adults of all age groups.

Know Your Risk and Management Options

Knowing that you are at a higher risk for certain cancers and understanding the signs and symptoms of those cancers could save your life.

Gastric Cancer

The symptoms of gastric cancer can be vague and are not specific to gastric cancer, but you should still know the symptoms of gastric cancer:

• Abdominal pain
• Decreased appetite
• Weight loss
• Indigestion
• Heartburn
• Excessive burping
• Feeling full or bloated easily
• Difficulty swallowing
• Nausea
• Vomiting
• Changes in bowel movements
• Blood in your stool

If you are at risk of gastric cancer due to a CDH1 mutation, consider your options.

• Screening: If you are diagnosed with a CDH1 mutation, you should have an upper endoscopy (a procedure done to visually examine your upper digestive system) and stomach biopsies (the removal of samples of stomach tissue for examination).
• If you choose to use screening as your management strategy for HDGC, you will likely have an upper endoscopy every 6 to 12 months.
  • This method is not very sensitive for detecting very early stages of stomach cancer but is important to be certain that there isn’t an obvious problem.
  • About 30 to 40 percent of the time, stage I cancer cells are identified on biopsies that are examined by a pathologist after endoscopy.
    • Because these cells may or may not progress to later stages of cancer, individuals found to have stage I cancer cells on upper endoscopy are encouraged to partner with healthcare providers who have HDGC expertise to discuss personalized options for next steps.
• Total Gastrectomy: It is recommended that individuals who have a CDH1 mutation and a family history of gastric cancer have a total gastrectomy, or removal of the stomach, to eliminate the risk of developing an advanced gastric cancer. This procedure is also referred to as a prophylactic total gastrectomy.
  • You should discuss this option with your health care providers as well as a health care team that specializes in HDGC and total gastrectomy.
  • Because gastrectomy can lead to long-term health and nutrition problems, when considering total gastrectomy your health care team should include providers with expertise in nutrition, gastric surgery and gastroenterology.
  • The timing of this surgery will depend on many factors.
• Find a team with HDGC expertise: No matter what option you choose, a team with genetic counselors, gastroenterologists, surgical oncologists, pathologists and nutritionists will be indispensable to help develop the care plan that is right for you.
  • It may be helpful to talk to a psychologist or therapist about the difficult decisions ahead of you and the emotions that come with a diagnosis of HDGC.

Breast Cancer

Know the symptoms of breast cancer:

• A lump in your breast
• Skin changes or dimpling of your breast
• Breast asymmetry
• Nipple pain or discharge
• Breast pain

If you are at risk of lobular breast cancer (LBC) due to a CDH1 mutation, consider your options.

• Screening: Recommended screening procedures include mammograms and MRIs of the breasts on a regular basis starting at age 30.
• Bilateral Mastectomy: Having a bilateral mastectomy (surgery to remove both breasts) to decrease breast cancer risk may be an option.
  • You should discuss these options with your health care providers as your decision will depend on many factors
  • Note that even with bilateral mastectomy, there is still a very small possibility that breast cancer will develop at a later point because not all at-risk breast tissue can be removed
• Find a team who is familiar with HDGC and LBC: This may include breast oncologists, surgical oncologists and pathologists who can help you develop a care plan that is right for you.
  • It may be helpful to talk to a psychologist or therapist about the difficult decisions ahead of you and the emotions that come with a diagnosis of a CDH1 mutation.

Other Risk Factors

Many factors can influence the risk of cancer. Modifiable factors, meaning factors that you can control, associated with an increased risk of stomach cancer include drinking three or more alcoholic drinks per day, eating foods high in salt or salt-preserved foods and having a high intake of processed or red meat. However, in the setting of CDH1 mutations it is not clear if these factors play a role in the development of cancer.

Diet and nutrition guidelines that may reduce the risk of stomach cancer in the absence of a CDH1 mutation include the following:

• Maintain a healthy weight
• Keep physically active
• Eat a variety of whole grains, vegetables, fruit (especially citrus fruits) and beans
• Avoid salt-preserved and high-salt (high sodium) foods
• Avoid sugar-sweetened beverages
• Limit processed and red meat consumption
• Limit your alcohol intake
• Avoid tobacco

Keep in mind that diet and lifestyle recommendations to reduce the risk of stomach cancer do not guarantee cancer prevention. People who have an inherited risk of stomach cancer need to follow additional guidelines from their health care team. Talk to your health care team about additional recommendations specific to you.

It is not known exactly how many people have HDGC. The frequency of HDGC also varies among different ethnicities. HDGC makes up only about 1% to 3% of all stomach cancer cases. Most patients with HDGC are diagnosed before the age of 40.

It is likely that 20 to 40 percent of individuals with HDGC have a mutation in the CDH1 gene. The CDH1 gene provides instructions for making a protein called epithelial cadherin or E-cadherin. This protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body. E-cadherin helps neighboring cells stick to one another (cell adhesion) to form organized tissues. E-cadherin has many other functions including acting as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.

People with HDGC caused by CDH1 gene mutations are born with one mutated copy of the gene in each cell. These mutations cause the production of an abnormally short, nonfunctional version of E-cadherin or alter the protein's structure. For diffuse gastric cancer to develop, a second mutation involving the other copy of the CDH1 gene must occur in the cells of the stomach lining during a person's lifetime. Women who are born with one mutated copy of the CDH1 gene have a 56 percent chance of acquiring a second mutation in the other copy of the gene and developing gastric cancer in their lifetimes; men have a 70 percent chance of acquiring a second mutation and developing gastric cancer.

When both copies of the CDH1 gene are mutated in a particular cell, that cell cannot produce any functional E-cadherin. The loss of this protein prevents it from acting as a tumor suppressor, contributing to the uncontrollable growth and division of cells. A lack of E-cadherin also impairs cell adhesion, increasing the likelihood that cancer cells will not come together to form a tumor but will invade the stomach wall and metastasize as small clusters of cancer cells into nearby tissues.

These CDH1 gene mutations also lead to a 40 to 50 percent chance of lobular breast cancer in women, a slightly increased risk of prostate cancer in men, and a slightly increased risk of colorectal cancer. It is unclear why CDH1 gene mutations primarily occur in the stomach lining and these other tissues.

About 60 to 70 percent of individuals with HDGC do not have an identified mutation in the CDH1 gene. In some individuals, mutations in other cancer-inducing genes cause HDGC, but in some cases, the mechanism is unknown.

Normal Function

The CDH1 gene provides instructions for making a protein called epithelial cadherin or E-cadherin. This protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body, such as the inside of the eyelids and mouth. E-cadherin belongs to a family of proteins called cadherins whose function is to help neighboring cells stick to one another (cell adhesion) to form organized tissues. Another protein called p120-catenin, produced from the CTNND1 gene, helps keep E-cadherin in its proper place in the cell membrane, preventing it from being taken into the cell through a process called endocytosis and broken down prematurely.

E-cadherin is one of the best-understood cadherin proteins. In addition to its role in cell adhesion, E-cadherin is involved in transmitting chemical signals within cells, controlling cell maturation and movement, and regulating the activity of certain genes. Interactions between the E-cadherin and p120-catenin proteins, in particular, are thought to be important for normal development of the head and face (craniofacial development), including the eyelids and teeth. E-cadherin also acts as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Breast cancer

Inherited mutations in the CDH1 gene increase a woman's risk of developing a form of breast cancer that begins in the milk-producing glands (lobular breast cancer). In many cases, this increased risk occurs as part of an inherited cancer disorder called hereditary diffuse gastric cancer (HDGC) (described below). Inherited mutations in the CDH1 gene are thought to account for only a small fraction of all breast cancer cases.

CDH1 gene mutations also occur commonly in lobular breast cancers in women without a family history of the disease. These genetic changes, known as somatic mutations, are not inherited. Somatic gene mutations are acquired during a person's lifetime and occur only in certain cells in the breast. Some of these genetic changes occur within the gene itself, while others turn off (inactivate) a region of nearby DNA that controls the gene's activity. Researchers believe that the resulting loss of E-cadherin protein may allow breast cells to grow and divide unchecked, leading to a cancerous tumor. A lack of this protein, which is critical for cell adhesion, may also make it easier for cancer cells to detach from a primary tumor and spread (metastasize) to other parts of the body.

Hereditary diffuse gastric cancer

More than 120 inherited mutations in the CDH1 gene have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer (HDGC). People with CDH1 gene mutations associated with HDGC have a 56 to 70 percent chance of developing stomach (gastric) cancer in their lifetimes. Women with these mutations also have a 40 to 50 percent chance of developing lobular breast cancer (described above). People with HDGC caused by CDH1 gene mutations are born with one mutated copy of the gene in each cell. An additional mutation that impairs the normal copy of the CDH1 gene is needed for cancer to develop. This mutation is a somatic mutation and is present only in cells that give rise to cancer.

The mutations that cause HDGC often lead to the production of an abnormally short, nonfunctional version of the E-cadherin protein or lead to the production of a protein with an altered structure. The loss of normal E-cadherin prevents it from acting as a tumor suppressor, contributing to the uncontrollable growth and division of cells. A lack of E-cadherin impairs cell adhesion, increasing the likelihood that cancer cells will invade the stomach wall and small clusters of cancer cells will metastasize into nearby tissues. In combination, the inherited and somatic mutations lead to a lack of functional E-cadherin and result in HDGC.

Blepharocheilodontic syndrome

At least five inherited CDH1 gene mutations have been identified in people with blepharocheilodontic (BCD) syndrome. This disorder is present at birth and causes abnormalities mainly affecting the eyelids and mouth, including openings on both sides of the upper lip (bilateral cleft lip) and an opening in the roof of the mouth (cleft palate). CDH1 gene mutations that cause BCD syndrome are thought to result in an abnormal E-cadherin protein that is quickly broken down. A shortage of E-cadherin protein impairs the interaction between E-cadherin and p120-catenin and affects craniofacial development, leading to the features of BCD syndrome. Despite the association of CDH1 gene mutations with increased cancer risk (see below), it is unclear whether people with BCD syndrome are at increased risk of developing cancer.

Ovarian cancer

MedlinePlus Genetics provides information about Ovarian cancer

Prostate cancer

MedlinePlus Genetics provides information about Prostate cancer

Other cancers

Somatic CDH1 gene mutations are also associated with an increased risk of other cancers, including cancers of the lining of the uterus (endometrium) or the ovaries in women, and prostate cancer in men. These CDH1 gene mutations are thought to result in a nonfunctional E-cadherin protein. A loss of functional E-cadherin in these cells prevents tumor suppression and cell adhesion, leading to rapid cell growth and metastasis.

In addition, a specific inherited variation in the CDH1 gene is thought to increase the risk of prostate cancer. It is unclear why CDH1 gene mutations increase the risk of cancer in certain tissues and not in others.

Other disorders

Individuals with inherited CDH1 gene mutations may have cleft lip, cleft palate, or both (orofacial clefting) without the other signs and symptoms of BCD syndrome and with or without a family history of HDGC (both described above). The CDH1 gene mutations in these individuals are thought to alter the E-cadherin protein and impair normal craniofacial development, leading to orofacial clefting. It is unknown why some people with orofacial clefting caused by CDH1 gene mutations have additional signs and symptoms while others do not.

Other Names for This Gene

• Arc-1
• CADH1_HUMAN
• cadherin 1, E-cadherin (epithelial)
• cadherin 1, type 1
• cadherin 1, type 1, E-cadherin (epithelial)
• calcium-dependent adhesion protein, epithelial
• CAM 120/80
• CD324
• CDHE
• cell-CAM 120/80
• E-cadherin
• ECAD
• LCAM
• liver cell adhesion molecule
• UVO
• uvomorulin

Genomic Location

The following list includes the most common signs and symptoms in people with hereditary diffuse gastric cancer (HDGC). These features may be different from person to person. Some people may have more symptoms than others, and they can range from mild to severe. This list does not include every symptom that has been described in the condition.

Signs and symptoms may include:

• Personal history of diffuse gastric cancer
• Family history of diffuse gastric cancer
• Personal or family history of cleft lip/palate and diffuse gastric cancer
• Personal or family history of lobular breast cancer

People with HDGC have an increased risk of developing gastric cancer compared to people without HDGC. The average age at diagnosis is in the late 30s or early 40s. Symptoms of gastric cancer can be difficult to recognize until it's in the advanced stages. These may include abdominal pain, nausea, and loss of appetite.

People with family members with HDGC can receive genetic testing to see if they have a mutation in the CDH1 gene, or other rarer mutations that are known to cause HDGC. Genetic counseling is recommended for people with two or more immediate family members diagnosed with diffuse gastric cancer or diagnosed with gastric cancer at a young age. Different types of CDH1 mutations are associated with certain risks, like developing cancer at a young age. To see if this information changes the management of your cancer and family members who may be at risk, please talk with your genetic counselor and doctor.

HDGC can be hard to diagnose because some of the more common imaging tests used to search for cancer in the stomach cannot pick up HDGC. This leads to HDGC being diagnosed at later stages when the cancer is more advanced. Symptoms can include:

• Stomach pain
• Nausea and vomiting
• Loss of appetite
• Weight loss
• Trouble swallowing

When HDGC has spread to other parts of the body, imaging tests and biopsies may be done to diagnose HDGC.

Imaging: If you have symptoms of HDGC, your doctor will use imaging scans such as ultrasound, CT, and PET to look at where the tumor is and how big it is. They will also check for signs that the tumor has spread to other parts of the body.

Biopsy: To check if the tumor is HDGC your doctor will do one or multiple biopsies, taking a small sample from the tumor with a needle. An expert, called a pathologist, will study cells from the sample under the microscope to see what kind of tumor it is.

Background

What are genes?

Genes are a biological material that provide instructions for how our bodies look and function. Genes are found in every cell of our bodies. Genes are made up of a chemical called deoxyribonucleic acid, or DNA.

What are gene variants?

DNA is made up of four building-block chemicals, labeled with the letters A, T, C and G. These letters of DNA need to be in a particular order for genes to work properly. Gene variants, or mutations, occur when the letters are out of order, added or missing.

• Gene variants may or may not affect the function of the gene
• Some gene variants can lead to benign or cancerous tumors
• A gene variant that contributes to the development of a disease is known as a pathogenic or likely pathogenic variant (PLP)

What is genetic testing?

Genetic testing is a type of medical test that looks at the order of the letters in your DNA to determine what gene variants you carry. This may help determine any diseases or disease risks that you have. Genetic testing can look at a specific gene or many genes at once.

What is a genetic counselor?

Genetic counselors have training in medical genetics and counseling to guide patients as they look for more information about how inherited diseases might affect them or their relatives. You can meet with a genetic counselor in person, by phone or by videocall.

A genetic counselor will help guide you through the process of getting a genetic test and interpreting its results.

You may also be able to meet with a doctor, nurse or physician assistant who specializes in cancer genetics, if that resource is available in your hospital or cancer center.

Who Would Benefit From Genetic Testing?

There are two main types of gastric cancer: diffuse and intestinal. You may benefit from genetic testing if you have been diagnosed with diffuse gastric cancer (DGC). If you have not had cancer but you have a blood relative (parent, sibling, grandparent, aunt, uncle or cousin) that has been diagnosed with diffuse gastric cancer then you may benefit from genetic testing. Having cases of intestinal gastric cancer and other types of cancers in the family, like breast cancer, can also be a reason to seek genetic testing. If you or a blood relative have been diagnosed with cancer, then it is recommended that you talk to a genetic counselor about whether genetic testing is right for you.

Genetic Testing for Hereditary Gastric Cancer  

Diffuse gastric cancer can run in families if there is a pathogenic variant in the CDH1 or CTNNA1 gene. If you or a relative has been diagnosed with diffuse gastric cancer, but no variant has yet been identified in the family, then genetic testing for variants in both the CDH1 and CTNNA1 genes is recommended. If a gene variant associated with diffuse gastric cancer has already been identified in a family member, then, in some cases, an individual can just be tested for that gene to see if they also have the same variant.

The CDH1 gene is found in humans and makes a protein that, when working normally, suppresses the growth of tumors in certain types of tissue, particularly stomach (gastric) and breast tissue. When the CDH1 gene has a pathogenic or likely pathogenic variant, its either fails to make the protein or it makes a protein that fails to function correctly. As a result, tissues are unable to suppress tumor growth that can lead to cancer. The CTNNA gene works similarly.      

There are other genes that are known to increase the risk of developing intestinal gastric cancer. These genes are APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, PMS2, SMAD4, STK11 and TP53. There is also early evidence to suggest that the genes ATM, BRCA1, BRCA2, CHEK2 and PALB2 may increase the risk of gastric cancer.

If no gene variant associated with gastric cancer has been identified in your family, your genetic counselor may recommend gene panel testing. Gene panel testing involves testing for more than one gene at the same time. Given that there are several genes associated with different forms of gastric cancer, gene panel testing is a common test that may be preferred by patients and health care providers. 

All genetic testing is performed on a blood or saliva sample to look for gene variants.

I’ve done genetic testing and have a pathogenic CDH1 variant. Now what?

If you have a PLP variant, you’ll want to consider your screening, surveillance and management options. In addition, it is important to consider what this means for your family members. Though everyone has two copies of the CDH1 gene, one from their father and one from their mother, it only takes one pathogenic variant in CDH1 for an individual to be at risk for cancer. This type of genetic inheritance is called an autosomal dominant pattern. This pattern means that parents, children and siblings of an individual with a CDH1 variant have a 50 percent chance of having that same variant in their genes.

Any relative 18 years old or older is eligible for genetic testing. Anyone considering genetic testing should receive appropriate education and counseling.

Testing children under the age of 18 can be considered based on cancer family history and parents’ preferences; the risks, benefits and limitations of testing children should first be discussed with a genetic counselor.

Reproductive options for individuals with a pathogenic variant in CDH1

If you are considering having children, you may be wondering if there are ways to avoid passing a pathogenic gene variant on to your children. Prior to becoming pregnant, it is recommended to meet with a genetic counselor who specializes in fertility to discuss prenatal diagnoses, the use of a donor or preimplantation genetic testing.

Preimplantation genetic testing (PGT) is a medical procedure that allows people who carry a pathogenic or likely pathogenic gene variant to have children without that variant. The PGT process begins with in vitro fertilization (IVF). Following IVF, when the embryos are about 5-7 days old, a few cells are removed from the outer part of the embryo and the DNA of those cells is checked for the presence of the genetic variant. Only embryos that do not carry the variant are implanted.

It is important to keep in mind that PGT can be an emotional and costly process that requires a commitment of time. Decisions around having children can be complex for individuals and couples.  

Legal Protections Against Genetic Discrimination

The Genetic Information Nondiscrimination Act (GINA) was signed into federal law in 2008. GINA prohibits health insurers and most employers from discrimination against individuals based on genetic information, including the results of genetic tests and family history information. According to GINA, health insurance companies cannot consider genetic information to be a preexisting condition; nor can they use it to make decisions regarding coverage or rates. GINA also makes it illegal for employers to use genetic information when making decisions about hiring, firing, promoting or other terms of employment. It is important to note that GINA does not apply to the individuals affected with a disease like cancer or those in the military, and it does not offer protections for life insurance, disability insurance and long-term care insurance.

Use this page to help guide the questions you ask your genetic counselor before you undergo any genetic tests. Bring a pen, and possibly a notebook, to your appointment. You can print and fill in answers to each question below and should feel free to add any other questions that you may want answered.

1. What type of genetic test would you recommend?
2. What does the genetic testing process involve?
3. How likely is it that I have a CDH1 or other cancer-related gene variant?
4. If I test positive for a CDH1 variant, what cancers am I at risk of developing?
5. What can I do to reduce my chance of developing cancer?
6. Does the test provide information about my risk for other diseases besides cancer?
7. If I haven’t been diagnosed with cancer and I test positive for an inherited cancer gene variant, does that mean I am going to be diagnosed with cancer?
8. If I haven’t been diagnosed with cancer and I test negative for a cancer gene variant, does that mean my cancer risk is not higher than average?
9. Is it possible for my results to be uncertain?
10. If I’ve already been diagnosed with cancer, can genetic testing help predict whether the cancer will come back?
11. If I get genetic testing now, do I need to get tested again in the future?
12. How will the results of my genetic test impact my family members?
13. What are my options to pay for genetic testing?
14. Can my health or life insurance company increase my rates if I test positive?
15. Should I obtain life insurance before undergoing genetic testing?

Because CDH1 gene variants are inherited, it is possible that other members of your immediate family carry the variant and are at risk, too. It can be tough to have conversations with family members about cancer and cancer risk but approaching the subject could save their life.

Below is a template for a letter to tell your family members about your genetic testing results. You can fill in and send the letter, changing anything you feel is appropriate, or use it as a guide for how to speak with them in person. In the letter, we name a few support organizations that you and your family may find helpful to check out; there may be others not listed here, and NCI cannot specifically endorse any particular organization.

We recommend that you provide your family with all the pages of your genetic test report. The information will be important for when any relatives speak with their health care provider or a genetic counselor.

Note that this information is only relevant to relatives related by blood, such as parents, children, grandparents, grandchildren, siblings, nieces, nephews, aunts, uncles and cousins.

Letter Template

Dear _______________,

I recently had genetic testing to help me understand my risk of developing cancer. I was tested for inherited variants (aka mutations) in the CDH1 gene. Variants in this gene cause most cases of hereditary gastric (stomach) cancer, and also increase the risk of breast cancer in women. My test identified a variant that runs in our family, relevant for anyone related by blood. As one of my relatives, you may have the same CDH1 variant and could benefit from genetic counseling and genetic testing for this variant. If you find out that you have the variant, you can take steps to reduce your risk of cancer.

I am writing to you and all of our relatives who are at risk to recommend speaking to a genetic counselor. CDH1 variants can be passed from parents to their children. Since I have the variant, my parents, children, sisters and brothers each have a 50% chance of having it. My other blood relatives (aunts, uncles, nieces, nephews and cousins) also are at risk to have the variant.

Now that I know that I have a CDH1 variant I can take steps to reduce my risk for developing gastric and breast cancer in the future. You could also benefit from knowing whether you have this variant. The first step is to discuss this with a genetic counselor who can provide you with more information about the implications of CDH1 genetic testing. You can find a genetic counselor who provides telehealth or in-person services close to you at https://findageneticcounselor.nsgc.org/.

If you have genetic testing and find out that you have a CDH1 variant, then you can consider joining a hereditary gastric cancer study being conducted at the National Cancer Institute. The study provides long term medical support for individuals with a CDH1 variant by health care providers such as surgical oncologists, gastroenterologists, dietitians, nurses, social workers and genetic counselors. You can visit this website to learn more about this study: https://clinicaltrials.gov/ct2/show/NCT03030404 and to begin the enrollment process send an email to foregut@mail.nih.gov.

To read more about CDH1 you can visit this patient resources page provided by the NCI Center for Cancer Research (https://ccr.cancer.gov/surgical-oncology-program/clinical-team/patient-resources-for-hereditary-diffuse-gastric-cancer) or visit the websites of gastric cancer advocacy organizations such as the DeGregorio Family Foundation, Debbie’s Dream Foundation, Hope for Stomach Cancer and No Stomach for Cancer.

While it can be concerning to learn that there is a risk for a genetic condition in our family, there are many resources available for families with CDH1, and I want to help make sure that our family knows about this important lifesaving information.

Sincerely,

Treatment for each patient will be unique. You should go to an expert in HDGC treatment to decide the best approach for your tumor. You can contact MyPART for help finding experts near you.

Surgery: Surgery is most commonly used to remove the stomach to reduce the risk of developing cancer. Usually, the entire stomach is removed to prevent the cancer from growing and spreading.

Chemotherapy: When surgery is not possible or when the cancer has spread, chemotherapy is used to treat HDGC.

The estimate of how a disease will affect you long-term is called prognosis. Every person is different and prognosis will depend on many factors, such as:

• Where the tumor is in your body
• If the cancer has spread to other parts of your body
• How much of the tumor was taken out during surgery

If you want information on your prognosis, it is important to talk to your doctor.

When HDGC is found when it is small, the survival rate is high. When HDGC is already large or has spread to other parts of the body, treatment is more difficult and the five-year survival rate is less than 20%. People with a mutated CDH1 gene have the option of having surgery to remove their stomach before developing HDGC to prevent getting cancer. This can cause life-long symptoms related to eating and digestion and should be discussed with your doctor and nutritionist.