Hereditary diffuse gastric cancer (HDGC)

Hereditary diffuse gastric cancer (HDGC) is a rare, inherited syndrome that mostly affects the lining of the stomach. This disorder increases the risk of developing diffuse gastric cancer, a rare form of stomach cancer, and lobular breast cancer, a less common form of breast cancer. Unlike the more common intestinal types of stomach cancer, which tend to form distinct, localized tumors, diffuse gastric cancer spreads throughout the stomach wall, often making it difficult to detect in the early stages.

It’s important to note that not every person with HDGC develops cancer, but the odds are higher than average. Interventions are available to monitor for cancer and reduce the cancer risk. Penn Medicine’s Gastrointestinal Cancer Genetics Program has been specifically designed to help provide state-of-the-art, proactive health management for individuals and families with HDGC syndrome.

For most people, HDGC syndrome doesn’t have noticeable symptoms in its early stages. When symptoms appear, they may include:

• Stomach pain or bloating
• Decreased appetite
• Difficulty swallowing
• Unintended weight loss
• Nausea
• Vomiting

All of our genes are in pairs. One copy in each pair is from our biological mother, and the other copy is from our biological father. Genes are instructions for how the body grows and functions. Some genes help determine traits like hair or eye color. Other genes may increase or decrease the chance of disease, such as developing cancer.

Inheriting a single mutation in one copy of the CDH1 gene causes HDGC. CDH1 is a gene that tells our cells how to make the protein E-cadherin, which is important for holding cells together in our bodies. Mutations in the CDH1 gene can lead to a dysfunctional or absent E-cadherin protein. When the E-cadherin protein doesn’t function properly, cells can act abnormally, contributing to the development of diffuse gastric cancer or lobular breast cancer.

A person with a CDH1 gene mutation has a 50 percent chance of passing the gene mutation to a child. If a child doesn’t inherit the CDH1 gene mutation, the mutations can’t be passed to the next generation—CDH1 gene mutations don’t skip a generation.

Recent research shows that the CTNNA1 gene is another potential genetic cause of HDGC syndrome. However, more research needs to be done to better understand the cancer risks associated with CTNNA1 gene mutations.

Individuals who may wish to consider genetic testing for CDH1 or CTNNA1 include those who have:

• Diffuse gastric cancer and a family history of at least one first-degree relative (parent, sibling, or child) or second-degree relative (grandparent, aunt, uncle, or grandchild) with gastric cancer
• A personal or family history of diffuse gastric cancer diagnosed before age 40
• A personal or family history of diffuse gastric cancer and lobular breast cancer diagnosed before age 50
• A family member with a CDH1 or CTNNA1 mutation

In addition to these criteria, there are other instances where genetic testing may also be appropriate. Talk with your Penn Medicine care team about your specific situation.

Penn Medicine’s Hereditary Diffuse Gastric Cancer Syndrome Program treatment team is dedicated to improving care for individuals and families with HDGC. Recent research from our program has investigated the use of endoscopic ultrasound in managing HDGC. Additional research has focused on the importance of pre-test counseling prior to CDH1 genetic testing, while other research has described the differing clinical recommendations provided to individuals who test positive for CDH1 mutations. Our program also published the first large-scale analysis of CTNNA1 sequencing on multigene panel testing, which is critical to better understand the cancer risks associated with this gene.