Gastric Cancer — Keeping It in the Family

Genetic predisposition to gastric cancer was first proven in families with recurrent diffuse gastric cancer, where the disease was found to segregate with germline mutations of the E-cadherin (CDH1) gene. Subsequent guidelines defining the various types of inherited gastric cancer predisposition syndromes have identified that these represent 1–3% of gastric cancer worldwide. Mutational analyses of families worldwide suggest that germline CDH1 mutations account for approximately 40% of hereditary diffuse gastric cancer. A significant proportion of these mutations are associated with functional derangement of the E-cadherin protein. The lifetime risk of gastric cancer in patients with CDH1 mutation has been estimated at 70–80%. Individuals from these families are also at increased risk of other cancers, including colon, ovarian, protate and breast (in particular, lobular carcinoma). In addition to genetic counseling, these patients should be offered prophylactic gastrectomies as currently available screening methods may not be sufficient to identify occult disease. Several other candidate genes are currently being tested for their roles in inherited gastric cancer syndromes.