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Hereditary Diffuse Gastric Cancer (HDGC) Syndrome Program

What is hereditary diffuse gastric cancer syndrome (HDGC)?

HDGC syndrome is a hereditary condition that increases the risk of diffuse gastric cancer and lobular breast cancer. Diffuse gastric cancer is a rare form of stomach cancer, in which cancer cells invade the lining of the stomach wall. Lobular breast cancer is a less common form of breast cancer in women.

Up to 40 percent of individuals with HDGC will have a detectable mutation in the CDH1 gene, and a much smaller percentage may have a mutation in the CTNNA1 gene.

It is important to note that not every person with HDGC syndrome develops cancer, but the odds of developing cancer are much greater than average. Interventions are available to monitor for cancer, as well as to reduce cancer risk.

Within Penn Medicine's Gastrointestinal Cancer Genetics Program, the Hereditary Diffuse Gastric Cancer Syndrome Program has been specifically designed to help provide state-of-the-art, compassionate care and proactive health management for individuals and families with HDGC.

HDGC Syndrome Management

As part of Penn Medicine's Gastrointestinal Cancer Genetics Program, the Hereditary Diffuse Gastric Cancer Syndrome Program is designed for individuals whose families meet criteria for hereditary diffuse gastric cancer syndrome (HDGC) and/or have a personal or family history of a CDH1 or CTNNA1 gene mutation. This program provides comprehensive evaluation with genetic testing (if applicable), in-depth discussion of the cancer risks associated with HDGC, a comprehensive cancer risk management plan, and ongoing follow-up.

HDGC Syndrome Program Treatment Team

Penn Medicine's Hereditary Diffuse Gastric Cancer Syndrome Program treatment team includes physicians, genetic counselors and other health care providers who provide care to the largest group of individuals with HDGC throughout the Philadelphia region.

Cancer Risk Assessment and Management:
(ongoing follow-up care including nutritional counseling post-gastrectomy)

Endoscopic Procedures:

Surgical Oncology:

High-risk Breast Cancer Surveillance:

Genetic Counseling/Testing:

Hereditary Diffuse Gastric Cancer (HDGC) Syndrome FAQs

Below you'll find the answers to frequently asked questions about Hereditary Diffuse Gastric Cancer syndrome and genetic testing.

What causes HDGC syndrome?

Genes are instructions for how the body grows and functions. Our genes are inherited (passed down) from our parents. Some genes help determine traits like hair color or eye color.

Other genes may increase or decrease the chance of disease, such as developing cancer. Some individuals with HDGC syndrome are born with a mutation (harmful genetic change) in the CDH1 gene. CDH1 is a gene that tells human cells how to make the protein E-cadherin, which is important for holding cells together in our bodies.

Individuals who are born with a CDH1 gene mutation are thought to have increased risk of diffuse gastric cancer and lobular breast cancer. Lifetime gastric cancer risk has been estimated between 30-80% for individuals with a CDH1 gene mutation, whereas lifetime breast cancer risk is around 40% for females with a CDH1 gene mutation. The risks related to HDGC syndrome may be reduced or managed through specialized medical care.

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

How is HDGC syndrome inherited?

All of our genes are present in pairs. One copy in each pair is from our mother, and the other copy is from our father. Inheriting a single mutation in one copy of the CDH1 gene causes HDGC syndrome. This is called dominant inheritance.

A person with a CDH1 gene mutation has a 50 percent chance of passing the gene mutation to a child. Men and women are equally at risk of inheriting a CDH1 gene mutation causing HDGC syndrome. If a child does not inherit the CDH1 gene mutation, the mutations cannot be passed along to the next generation (CDH1 gene mutations do not skip a generation).

When should genetic testing for HDGC syndrome be considered?

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

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

What steps should families with HDGC syndrome take to reduce cancer risk?

Individuals with HDGC syndrome should be managed at a multi-disciplinary specialty center, such as Penn Medicine, given the complex and nuanced nature of these conditions. Management plans are individualized, and recommendations may include endoscopic surveillance, risk-reducing surgery, and/or enhanced breast cancer screening.

Does Penn Medicine have any resources for HDGC syndrome patients?

We recommend that HDGC syndrome patients who undergo gastrectomy or are considering gastrectomy attend the Gastrectomy Support Group, which is held every one-to-two months at the Hospital of the University of Pennsylvania/Perelman Center for Advanced Medicine.

If you are interested in learning more or attending, contact Caitlin Perch, DNP, CRNP at caitlin.perch@pennmedicine.upenn.edu.

HDGC Syndrome Research

The Hereditary Diffuse Gastric Cancer Syndrome Program at Penn Medicine 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 syndrome, as well as explored the role that endoscopy plays in the management of HDGC syndrome. These studies have highlighted that further research to improve surveillance for diffuse gastric cancer is crucial.

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.