hereditary diffuse gastric cancer

What Does It Mean to Test Positive for a CDH1 Mutation?

Mutations in the CDH1 gene are associated with hereditary diffuse gastric cancer. Individuals with CDH1 mutations have an increased risk to develop a type of stomach cancer called diffuse gastric cancer. Women with CDH1 mutations also have an increased risk to develop a specific type of breast cancer called lobular breast cancer. However, it is important to understand that the risk for cancer is not 100%, which means that not everybody with a CDH1 mutation will develop cancer.

What Are the Cancer Risks Associated with a CDH1 Mutation?

Both men and women with CDH1 mutations are at increased risk of developing diffuse gastric cancer. Women with CDH1 mutations also have an increased risk for the lobular type of breast cancer. There is also evidence that there is an increased risk for colon cancer in CDH1 mutation carriers.

In most cases, the risk for cancer is reported as a range. Precise risk estimates are not available at this time because further research is needed to investigate how environmental or other genetic factors influence cancer risks among individuals with CDH1 mutations.

For Men and Women:

For individuals who have never had a cancer diagnosis, the lifetime risk of developing a CDH1-related cancer is significantly increased over the general population's risk.

The lifetime risk of developing diffuse gastric cancer is estimated to be 67% for men and 83% for women, with an average age of diagnosis of 38 years. Diffuse gastric cancer has also been detected as early as the teenage years.

Women have an estimated 39 to 52% lifetime risk for lobular breast cancer, with an average age of diagnosis of 53 years.

Cancer Type Cancer Risk Average Age of Onset General Population Risk
Gastric (Diffuse Type) 67 to 83% 38 Years < 1%
Female Breast (Lobular Type) 39 to 52% 53 Years 12.4%

The risk of colon cancer in individuals with a CDH1 mutation may be greater than that of the general population; however, the specific percentage of risk is not clearly understood and may be limited to individuals with a family history of colon cancer.

What Cancer Screening and Risk-Reducing Options Are Available?

CDH1 mutation carriers are encouraged to work with a multidisciplinary team of specialists to manage their cancer risks. Current practices include:

  • Surgical removal of the stomach (prophylactic gastrectomy) between the ages of 18 and 40 is recommended based on guidelines from the International Gastric Cancer Linkage Consortium. Prior to this surgery, individuals should undergo screening by endoscopy with random gastric biopsies every 6 to 12 months.
  • For individuals with a family history of colon cancer, colonoscopy screening is recommended starting at age 40 or earlier, depending on the age of diagnosis in family members. Colonoscopy should be repeated every three to five years or more frequently based on findings from previous studies.
  • For women, annual mammograms with consideration of 3D mammogram (tomosynthesis) and consideration of breast MRIs are recommended beginning at age 30 or earlier, based on family history. Women also have the option of prophylactic mastectomy.

What Is the Chance That Family Members of CDH1 Mutation Carriers Have the Same Mutation?

CDH1 mutations are passed down in a family. This means that family members of CDH1 mutation carriers may have the same mutation and may also be at increased risk of developing cancer. More rarely, a sporadic genetic mutation occurs in a single family member, which means an individual could be the first person in a family to have a CDH1 mutation. In either case, it is important for CDH1 mutation carriers to discuss genetic test results with family members.

  • Close blood relatives of CDH1 mutation carriers, such as parents, siblings, and children, have a 50% chance of having the same mutation.
  • For individuals who are determined to be the first affected member of a family, which can occur in a small percentage of individuals, testing is still indicated for biological children who have a 50% chance to inherit the CDH1 mutation.
  • Distant relatives, such as aunts, uncles, grandparents, and cousins, also have a chance of having the same CDH1 mutation.
  • A physician or a genetic counselor can help mutation carriers determine whether the mutation was more likely to have been inherited from the maternal or paternal side of the family. In general, the mutation will only be found on one side of the family, and it is more likely to be on the side of the family that has a history of stomach (gastric) or breast cancer.

Genetic testing of family members can help determine which family members are at increased risk for cancer and may benefit from the screening and/or risk reduction options discussed above. Family members who test negative for a known familial CDH1 mutation likely have the same risk for cancer as the general population and can follow the general population's screening guidelines.

What Else Should CDH1 Mutation Carriers Know?

Mutation carriers who are interested in options to prevent passing their mutation to future children may wish to consider preimplantation genetic diagnosis (PGD). PGD is a procedure that involves in vitro fertilization (IVF) and can determine if an embryo carries the genetic mutation present in a family. Determining which embryos carry the family mutation may allow a mutation carrier to prevent the condition from being passed to future children. The decision to undergo PGD is personal. Mutation carriers and their family members can talk with a healthcare provider to learn more about their reproductive options.