Hereditary Diffuse Gastric Cancer (HDGC)

What is hereditary diffuse gastric cancer syndrome (HDGC)?

Hereditary diffuse gastric cancer (HDGC) is a genetically inherited cancer syndrome that raises your lifetime risk of developing gastric (stomach) cancer by an estimated 70%. Women and people assigned female at birth (AFAB) who inherit the syndrome also have an increased risk of developing lobular breast cancer (LBC), estimated at 42%.

People with hereditary diffuse gastric cancer syndrome inherit a mutated gene from one of their biological parents. It’s usually a gene called CDH1, though sometimes, a different gene is involved. CDH1 is a tumor suppressor gene. When it’s mutated, it doesn't function correctly to keep cancer in check.

Diffuse gastric cancer

Diffuse gastric cancer is a type of stomach cancer that develops in small clusters of cells that are widely diffused (spread) throughout your stomach lining. Instead of forming solid tumors, it thickens and hardens your stomach lining overall. As it grows, it spreads into the deeper layers of your stomach wall.

This type of stomach cancer often goes undetected because it doesn’t show up on routine imaging tests. It doesn’t typically cause symptoms until the advanced stages. By this time, it’s likely to have already spread (metastasized) through your stomach wall to other nearby tissues, such as your liver and bones.

How common is this condition?

Hereditary diffuse gastric cancer syndrome is estimated to occur in 5 to 10 per 10,000 births. About 20% of all gastric cancers are diffuse, and about 2% of all diffuse gastric cancers are hereditary. Stomach cancer in general is more common in Asia than in the West, but HDGC is more common in the West.

What are the symptoms of hereditary diffuse gastric cancer syndrome?

Symptoms of diffuse gastric cancer may not show up until it’s metastasized. That’s why it’s important to be aware of the risk of inheriting the syndrome. Cancer in HDGC also tends to develop in relatively younger people, compared to non-hereditary cancer. Most people are diagnosed before the age of 40.

Symptoms include:

• Stomach pain (especially in your upper left abdomen).
• Bloated stomach.
• Nausea and vomiting.
• Loss of appetite.
• Weight loss.
• Fatigue.
• Difficulty swallowing.
• Blood in your poop.
• Vomiting blood.
• Jaundice (yellow tint to your eyes and skin).

Sometimes, a cleft lip or cleft palate can be an early sign of the syndrome. This birth defect can occur with the same gene mutation. Although most cases of cleft lips or palates are unrelated to HDGC, being born with one may raise suspicion of the syndrome if you have any family history of these cancers.

What causes hereditary diffuse gastric cancer syndrome (HDGC)?

HDGC is a genetic disorder. It happens when a mutation in one of your tumor-suppressing genes changes your DNA programming. Tumor-suppressing genes are supposed to provide your cells with the instructions they need to control cell division and growth. When they can’t, cancer can be the result.

You inherit the mutated gene with the faulty programming from a biological parent. An inherited mutation is also called a germline mutation. It affects the genetic coding in your reproductive cells, which are also called germ cells. These cells make copies of themselves during reproduction.

How do you inherit hereditary diffuse gastric cancer syndrome?

HDGC is an autosomal dominant condition, which means you only need one copy of the mutated gene to inherit the syndrome. You can inherit it from either parent, on either side. If one of your biological parents has the mutation, there’s a 50% chance they’ll pass it on to you or any other biological children.

Does everyone who inherits the mutation develop cancer?

No. The germline mutation that you inherit from a parent affects one copy of the tumor-suppressing gene in each cell. But each cell has two copies of the gene, one from each parent. Unless you inherit the same mutation from both parents, you still have one copy of the gene that functions normally.

For cancer to develop, a second mutation has to take place within tissues where that type of cancer forms (your stomach lining or breast lobules). This happens during your lifetime. The second mutation, called a somatic mutation, affects the other copy of the tumor-suppressing gene, which disables it.

What causes the second mutation?

The short answer is that we don’t know, but there’s probably a variety of factors involved. Environmental exposures often play a part in “triggering” genetic diseases. Other genes may also play a part. In some families carrying the HDGC gene, cancer is much more prevalent than in other families.

Environmental risk factors for developing stomach cancer include:

• Smoking.
• Heavy alcohol use.
• Red meat consumption.
• H. pylori infection.

What is the screening process for hereditary diffuse gastric cancer?

If you don’t have symptoms yet, but have reason to believe you’re at risk, a healthcare provider may recommend you for HDGC screening. You might have a known family history of one of these cancers, or you might have already had genetic testing that identified germline mutations in the CDH1 gene.

Your provider will calculate your risk based on your family history and/or genetic testing. They may want to check for cancer precursors in your tissues, such as lobular carcinoma in situ (LCIS) or signet-ring-type cells in your stomach lining. These are precancerous tissue changes that can later progress to cancer.

How is hereditary diffuse gastric cancer syndrome diagnosed?

If you have symptoms of diffuse gastric cancer, a healthcare provider will look for evidence of cancer in your stomach lining. They’ll take tissue samples to examine under a microscope. If they find diffuse gastric cancer, and if you have other relatives who’ve developed the same cancer, they might recommend genetic testing.

The CDH1 gene mutation is currently associated with about 40% of HDGC cases. Other mutations are likely involved, but CDH1 is the one we know and recognize. If you have it, it’s a sure way to recognize HDGC. But you can still be diagnosed without it if your family shows a strong pattern of familial diffuse gastric cancer.

What tests diagnose HDGC?

Diagnostic tests may include:

• Genetic testing. A genetic test is a blood test that analyzes a sample of your blood for genetic mutations associated with known genetic diseases. Some people choose to have a genetic blood test because they have known genetic diseases in their family. Other people don’t necessarily know their family health history. They may choose to have a genetic blood panel for their own general information or because they want to plan for biological children.
• Upper endoscopy. An upper endoscopy (EGD test) is a way to closely examine and take tissue samples of the inside lining of your upper gastrointestinal tract. This is necessary to diagnose stomach cancer, especially the diffuse type that lurks in small clusters of cells in your stomach lining. A gastroenterologist or colorectal surgeon performs an endoscopy. They send a tiny camera on the end of a long catheter — an endoscope — down your esophagus into your stomach. They can take tissue samples through the endoscope. Even with these methods, diffuse gastric cancer can be tricky to catch. Because it’s so spread out, your endoscopist might not be able to see it or snag it in their tissue samples. An endoscopist looking for diffuse gastric cancer should be specially trained and experienced.
• Breast MRI. Healthcare providers recommend a breast MRI to look for lobular breast cancer, as it doesn’t always show up on a regular mammogram. If your radiologist sees anything unusual on the MRI, they’ll flag it, and another healthcare provider will take a tissue sample.
• Biopsy. Your healthcare provider will send tissue samples to a lab to analyze under a microscope. The biopsy will confirm whether the tissue sample has any cancer in it.

What happens after being diagnosed with HDGC?

If you already have cancer, your provider will discuss treatment options with you. If you don’t have cancer yet, but you have the syndrome, your provider will recommend regular cancer screening tests as listed above. Preventive surgery is another option that you can discuss with your healthcare provider.

How is diffuse gastric cancer treated?

Surgery is usually the first-line treatment for cancer that can be physically removed. If you have HDGC, your provider will often recommend a total gastrectomy — surgery to remove your whole stomach. This is due to the high risk of HDGC lurking and spreading too far in your stomach lining before it’s caught.

During a total gastrectomy, your surgeon will remove your stomach and connect the end of your esophagus directly to your small intestine. You can live without a stomach, though there will be side effects. After surgery, you may have adjuvant therapies, such as radiation therapy or chemotherapy.

People with HDGC who were assigned female at birth are also at risk of developing lobular breast cancer (LBC). Treatment for these people will also include close surveillance for signs of LBC. If you have LBC, treatment will usually begin with breast cancer surgery, followed by adjuvant therapy.

Is there any way to prevent hereditary diffuse gastric cancer?

If you have a CDH1 gene mutation, which is associated with a high risk of developing cancer, there are a few preventive actions that you can take. For people without this specific gene mutation, the risk and protocols aren’t clearly defined. You can discuss your personal risk and options with your provider.

Prophylactic surgery

If you’re at least 20 years old and otherwise healthy, and you have confirmed HDGC, your provider might recommend a prophylactic total gastrectomy. Although losing your stomach does have side effects for your digestive system, these side effects are easier to manage than diffuse gastric cancer.

People who aren’t ready to take this step can take a wait-and-watch approach, which involves frequent upper endoscopy exams with multiple random biopsies. But even this level of surveillance doesn’t always detect hereditary diffuse gastric cancer in the early stages when treatment is more likely to be effective.

Side effects of total gastrectomy include:

• Dumping syndrome. When food enters your small intestine directly from your esophagus, it comes in more rapidly than it usually would. This can cause drastic hormonal shifts in your digestive system, which may cause symptoms such as nausea, diarrhea and low blood sugar. Adjusting your eating habits can help with these symptoms, and they usually ease over time.
• Malabsorption and malnutrition. A total gastrectomy removes the part of your gastrointestinal tract where acids and digestive enzymes break food down for absorption. When this part of the process is missing, food may not break down well enough for all the nutrients to be absorbed. Malabsorption can lead to malnutrition. Diet and nutritional supplements can help with this.

Genetic counseling and family planning.

People with the CDH1 gene mutation may benefit from genetic counseling to discuss family planning. Genetic counseling can help you understand the risks of passing HDGC to a biological child. If you do plan to have biological children, selective IVF (in vitro fertilization) is one option for managing that risk.

In IVF, eggs and sperm are removed from potential parents and fertilized in a lab. After embryos develop, a provider can remove one cell from each embryo and test it for the CDH1 mutation. Parents can choose to select embryos without the mutation to transfer to the birthing parent’s uterus.

What is the prognosis with hereditary diffuse gastric cancer syndrome?

The prognosis depends on finding and treating cancer in the early stages. This can be difficult, even with diligent surveillance. When diffuse gastric cancer is caught and treated early, the five-year survival rate is over 90%. When it’s caught later, after invading your stomach wall, the rate is less than 30%.

A note from Cleveland Clinic

Finding out that you have a hereditary diffuse gastric cancer syndrome (HDGC) can bring many heavy feelings and decisions to bear. These may involve your family as well as yourself. Take your time sorting through it all, and ask as many questions as you need. Your healthcare team is here to help you find your own best way forward.