Hereditary Diffuse Gastric Cancer

Approved by the Cancer.Net Editorial Board , 01/2020

What is hereditary diffuse gastric cancer?

Hereditary diffuse gastric cancer (HDGC) is a rare inherited condition associated with an increased risk of gastric (stomach) cancer .

The stomach is located in the upper abdomen and plays an important role in digesting food. When food is swallowed, it is pushed down the muscular tube that connects the throat with the stomach, called the esophagus, and enters the stomach. The muscles in the stomach mix the food and release gastric juices that help break down and digest the food. The food then moves into the small intestine for further digestion. Some people commonly refer to the stomach as the entire abdomen. However, doctors make a distinction between the stomach, which is an organ, and the abdomen, which is the area of the body between the chest and pelvic bones that holds many organs.

Diffuse gastric cancer is a specific type of stomach cancer, sometimes also called “signet ring cell gastric cancer” or “linitis plastic.” The word "diffuse" is used because this cancer tends to affect much of the stomach, rather than staying in 1 area of the stomach. Approximately 20% of all stomach cancers are diffuse gastric cancers, and a small number of these are due to HDGC. The average age for someone with HDGC to be diagnosed with stomach cancer is 38, although it can be diagnosed much earlier or later than that. Gastric cancers not associated with this syndrome tend to occur in people older than 60. Women with HDGC also have an increased risk of lobular breast cancer . Some people with HDGC may also have had a cleft lip or cleft palate at birth, although the vast majority are unrelated to HDGC.

What causes HDGC?

HDGC is an inherited genetic condition that is rare. This means that the cancer risk and other features of HDGC can be passed from generation to generation in a family. The gene most commonly associated with HDGC is called CDH1 . A mutation (alteration) in the CDH1 gene gives a person an increased risk of developing gastric cancer and other cancers associated with HDGC. Researchers believe that other genes, including CTNNA1, may be associated with HDGC. Studies are ongoing to learn more about all of these genes, and testing for inherited genetic mutations in these newer genes is currently not recommended except in clinical trials.

How is HDGC inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. HDGC follows an autosomal dominant inheritance pattern, in which a mutation happens in only 1 copy of the gene. This is called a germline mutation. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation. However, if the parents test "negative" for the mutation (meaning each person’s test results found no mutation), the risk to the siblings significantly decreases but their risk may still be higher than an average risk.

Options exist for people interested in having a child when a prospective parent carries a gene mutation that increases the risk for this hereditary cancer syndrome. Preimplantation genetic diagnosis (PGD) is a medical procedure done in conjunction with in-vitro fertilization (IVF). It allows people who carry a specific known genetic mutation reduce the likelihood that the child will inherit the condition. A woman’s eggs are removed and fertilized in a laboratory. When the embryos reach a certain size, 1 cell is removed and is tested for the hereditary condition in question. The parents can then choose to transfer embryos which do not have the mutation. PGD has been in use for over 2 decades and has been used for several hereditary cancer predisposition syndromes. However, this is a complex procedure with financial, physical, and emotional factors to consider before starting. For more information, talk with an assisted reproduction specialist at a fertility clinic.

How common is HDGC?

The specific number of families with HDGC is unknown. The overall incidence of gastric cancer varies in different parts of the world. In the United States, it is estimated that less than 1% of the population will develop stomach cancer of any kind; only a small fraction of these will be due to HDGC. The highest rates of gastric cancer in the world are in China, Japan, and other countries in Southeast Asia, as well as in Central and South America.

How is HDGC diagnosed?

Guidelines for the diagnosis of HDGC syndrome have been proposed, but may change over time as more is learned about this condition. Currently, the diagnosis of HDGC is suspected, and CDH1 genetic testing should be considered, if a person or family meets any of the criteria listed below:

  • Families with 2 or more cases of stomach cancer, with at least 1 being diffuse gastric cancer

  • A person diagnosed with diffuse gastric cancer before age 40

  • Personal or family history of both diffuse gastric cancer and lobular breast cancer, if at least 1 person was diagnosed before age 50

  • Families with 2 or more cases of lobular breast cancer diagnosed before age 50

  • A person diagnosed with multiple different lobular breast cancers before age 50

  • A person with diffuse gastric cancer and a personal or family history of a cleft lip or cleft palate

Genetic testing for mutations in the CDH1 gene is available. However, only about 20% to 30% of families that appear to have HDGC will have a mutation found in the CDH1 gene. Therefore, both clinical and genetic aspects must be considered in counseling individuals about the potential for their family to have HDGC. Talking with a specialist who has training in genetic diseases and conditions, called a genetic counselor or geneticist, who is familiar with the syndrome is recommended.

What are the estimated cancer risks associated with HDGC?

Not everyone who inherits a gene mutation for HDGC will develop cancer. In people who have a mutation in the CDH1 gene, the lifetime risk for diffuse gastric cancer is estimated to be 67% to 70% for men and 56% to 83% for women by age 80. Women with a mutation in the CDH1 gene have about a 39% to 52% risk of developing lobular breast cancer by age 80. Although some earlier studies suggested a possible link to risks of colon and/or rectal cancer, the current findings suggest that there is likely no increased risk for these cancers in people with an inherited CDH1 mutation.

What are the options for reducing cancer risks associated with HDGC?

Given the increased risk of cancers associated with germline mutations in CDH1 , it is recommended that people found to have this genetic mutation (called carriers) discuss the most appropriate strategies to reduce cancer risks with their health care team:

  • Stomach cancer : Endoscopic tests are when a thin, lighted tube is guided through the body’s gastrointestinal system to look for cancer. Although a baseline upper endoscopy exam (esophagogastroduodenoscopy or EGD ) is recommended for carriers, previous studies have shown that screening endoscopy exams often miss early-stage diffuse gastric cancers.

    Therefore, since endoscopic surveillance can be ineffective for preventing or detecting early-stage diffuse gastric cancers, individuals with a germline CDH1 mutation should consider having their stomach surgically removed, also known as prophylactic total gastrectomy, even if their endoscopy is normal. This type of surgery is the only proven effective way to prevent diffuse gastric cancer in individuals with HDGC. However, it is important to know that surgical removal of the stomach results in permanent changes to the digestive tract and can be associated with long-term side effects. It is very important for each patient to talk with their doctor about what tests and procedures would be appropriate for their individual care.

    People who decide not to have surgery to remove the stomach may consider an intensive surveillance schedule with their doctor, with an annual EGD with multiple (more than 30) mucosal biopsies. Both the surgical and endoscopic management of people with known or suspected HDGC are best performed in centers with expertise in care of people with this syndrome.

  • Additional screening for women: Women at risk for HDGC are at high risk for lobular breast cancer and should talk with their doctor about breast cancer screening options at the age of 30, or 10 years before the age of the youngest breast cancer diagnosis in the family. It is not yet clear what the best breast cancer screening strategy is for women with a CDH1 mutation. Screening options include:

    • Monthly breast self-examinations

    • Clinical breast examinations performed by a doctor or nurse every 6 months

    • Regular breast imaging with mammograms , ultrasound , and/or a breast magnetic resonance imaging (MRI)

Since lobular breast cancer can be difficult to detect with a mammogram, breast MRI is recommended for breast cancer screening for women with a CDH1 mutation. Surgical removal of the breasts, called prophylactic mastectomy, is sometimes recommended to reduce a woman’s risk of breast cancer. Women should discuss options for reducing their breast cancer risk with their doctors.

Learn more about what to expect when having common tests, procedures, and scans .

Questions to ask the health care team

If you are concerned about your risk of cancer, talk with your health care team. Consider asking your health care team the following questions:

  • What is my risk of developing stomach cancer?

  • What is my risk of developing other types of cancer?

  • What can I do to reduce my risk of cancer?

  • What are my options for cancer screening and cancer prevention?

If you are concerned about your family history and think you or other family members may have HDGC, consider asking the following questions:

  • Does my family history increase my risk of stomach cancer?

  • Does it suggest the need for a cancer risk assessment?

  • Will you refer me to a genetic counselor or other genetics specialist?

  • Should I consider genetic testing ?