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CDH1 is the only gene known to be associated with HDGC at this point in time, and only accounts for one-third to one-half of families with HDGC. Mutations of CDH1 have now been found over 100 families of diverse ethnic background, European, African American, Pakistani, Japanese, Korean and others.
Sequence analysis of the CDH1 gene has been available for several years on a research basis, and is now performed on a clinical basis through the Stanford Molecular Diagnostics Laboratory. A parent who carries a CDH1 mutation will have a 50% chance of passing on the mutation to each of their children. Most CDH1 families will have several generations of relatives affected, but it is possible to have a carrier parent who has not been diagnosed with gastric cancer or breast cancer. In addition, an individual with HDGC may have the disorder as a result of a new (de novo) gene mutation. This means the individual has a new change in one of their CDH1 genes that occurred prior to their conception but was not present in either parent.
For families that meet criteria 1 or 2, above, approximately 30-40% have been found to carry CDH1 mutations. Individuals meeting criteria 3 (no family history, gastric cancer less than 35 years old) have had a 10-20% chance of harboring a CDH1 mutation.
Genetic testing ideally should begin with a relative who has had gastric or lobular breast cancer to determine whether a CDH1 mutation is associated with their cancer. If a mutation is found, then unaffected relatives can be confident that the CDH1 test will accurately predict whether they have inherited HDGC or not. However, given the poor outcomes of individuals diagnosed with gastric cancer, many families do not have a living affected relative, and will need to consider CDH1 testing that may be inconclusive. Testing at-risk children younger than 18 from HDGC families is generally not recommended. However, there have been isolated reports of teenagers being diagnosed with diffuse gastric cancer, and so individual situations will need to be carefully discussed with the genetic counselor. Learn more about genetic testing and genetic counseling.
Other hereditary cancers
Gastric cancers have also been found in other hereditary cancer syndromes. For example, up to 10% of hereditary non-polyposis colon cancer (HNPCC) families include gastric cancers, though mostly of the "intestinal" pathologic type. In addition, Li-Fraumeni syndrome (p53 gene), familial adenomatous polyposis (APC gene) and Peutz-Jehgers syndrome (STK11 gene) all exhibit elevated rates of gastric cancers compared to the general population. The incidence of HDGC in the general popoulation remains to be well-defined, but HDGC probably accounts for only 1-3% of gastric cancers. Estimates suggest that up to 10% of patients diagnosed with gastric cancer will have some family history of gastric cancer. Many of these will likely be attributable to other gastric cancer genes and/or environmental factors that families tend to share.