Hereditary Diffuse Gastric Cancer and CDH1 Gene Mutations

About 30% of families with HDGC have a mutation (also known as a pathogenic variant) in a gene called CDH1, a tumor suppressor gene on chromosome 16 that normally encodes for a protein called E-cadherin. We have two copies of the CDH1 gene, one from each of our parents.  The normal function of E-cadherin is to allow cells and tissues to adhere to one another. When there is a mutation in the CDH1 gene, the function of the E-cadherin protein is disrupted, often resulting in the uncontrollable growth of abnormal (cancer) cells. A mutation in the CDH1 gene increases the risk of developing gastric cancer and lobular breast cancer. A smaller portion of HDGC is caused by mutations in the CTNNA1 gene.

Inheritance of the CDH1 gene mutation follows an autosomal dominant pattern, meaning that children of mutation carriers have a 50% chance of inheriting the gene, and a 50% chance of not inheriting it. Current estimates suggest up to three out of every four CDH1 gene mutation carriers will develop gastric cancer. 

Stomach cancer is one of the most common types of cancers in Southeast Asia, Central and South America. However, most cases of gastric cancer are not the diffuse type.  An estimated 1 to 3% of gastric cancer cases are diffuse.

Through genetic counseling and testing, we can identify mutations in the CDH1 gene. This test requires a blood or sputum sample. Targeted genetic testing for the CDH1 gene can be done based on family history of gastric cancer or a known familial mutation. However, CDH1 mutations are often identified when someone has panel testing, or when multiple genes are tested at once. Each family and each individual within that family is unique. A genetic counselor can evaluate your personal and family history of cancer and discuss the risks, benefits and limitations of genetic testing for CDH1.

Exact risks of cancer are difficult to estimate and vary between families with HDGC. Some studies have shown that men with the CDH1 gene variant and a strong family history of stomach cancer have up to a 70% risk of having diffuse gastric cancer in their lifetime, while women have up to a 56% risk of having diffuse gastric cancer and around 40% risk of lobular breast cancer in their lifetime. These cancers can affect all age groups, sometimes as early as the teens or twenties. Although some earlier studies have suggested a possible link to other cancers like colon and/or rectal cancers, the current findings suggest there is likely no increased risk for these cancers in people with an inherited CDH1 mutation.

Once an inherited CDH1 gene variant is detected in a person, a multidisciplinary team of experts comprised of surgeons, gastroenterologists, genetic counselors, nutritionists and pathologists, such as the team at the UChicago Medicine Gastrointestinal Cancer Risk and Prevention Clinic, can provide personalized recommendations. These options vary greatly by patient, but often include: 

• Endoscopic surveillance with random biopsies. This method of surveillance involves being sedated and having samples of the stomach lining biopsied to attempt to identify cancerous cells. However, this method is like “looking for a needle in a haystack” due to the diffuse nature of the cancer.  It can be difficult to identify these cells by taking biopsies because there are usually no visual differences of the stomach that can be seen with a scope to help target the biopsies. Therefore, the best way we have to reduce the risk of gastric cancer in CDH1 carriers is to have surgery.
• Surgery. If you have an increased cancer risk based on criteria met (a strong family history and CDH1 gene variant), your doctor may recommend a prophylactic (preventive) total gastrectomy. During a total gastrectomy, the entire stomach is removed and a part of the small bowel is then extended straight up to meet the esophagus. The cut end of the duodenum is then reconnected to the small bowel. 
  
  Life after surgery is very manageable, and while not having a stomach may seem daunting, over time the body will adjust to the "new normal." Your care team will discuss post-surgery recommendations with you, such as nutritional needs. 
• Breast cancer surveillance. Managing your breast cancer risk through breast surveillance is important for women in HDGC families. It is recommended that women affected by a CDH1 gene mutation meet with a breast oncologist or breast surgeon for yearly clinical breast exams and to talk about screening for lobular breast cancer. Beginning at age 30, active surveillance may include screening breast MRIs, in addition to annual mammograms and medication therapy. Some patients may even consider preventative mastectomy as an option, but this is not routinely recommended for CDH1 mutation carriers.

Receiving care from a team of stomach cancer specialists who are experts in the field of HDGC and have an understanding of the CDH1 gene mutation is essential. Our Gastrointestinal Cancer Risk and Prevention Clinic offers a personalized clinical and genetic testing assessment for patients and families who may be at risk for developing stomach cancer due to genetic factors. For individuals with HDGC, our multidisciplinary and integrated team provides comprehensive and evidence-based care. If you are concerned about your risk of cancer or family history, talk with your health care team.