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Gastric cancer is the fourth most common malignancy worldwide and the second most common cause of cancer-related death.1 Histologically, gastric cancer may be classified as either of the diffuse type or of the intestinal type. The intestinal type is linked to environmental risk factors and advanced age. The diffuse type (typically associated with signet ring cell histology and/or the clinical picture of linitis plastica in advanced stages) occurs in younger patients and can have a hereditary component. Partly due to a significant decrease in the incidence of the more common intestinal type, the overall incidence of gastric cancer has decreased. However, the incidence of diffuse gastric cancer has either increased or remained stable. Approximately 10% of gastric cancer cases demonstrate familial clustering, and 1% to 3% meet the criteria for hereditary diffuse gastric cancer (HDGC).2,3

Hereditary diffuse gastric cancer is a genetic cancer susceptibility syndrome diagnosed by one of the following: (1) two or more documented cases of diffuse gastric cancer in first- or second-degree relatives, with at least one diagnosed before the age of 50 and (2) three or more cases of diffuse gastric cancer in first- or second-degree relatives, independent of age of onset. The average age of onset of HDGC is 38 years. It is inherited in an autosomal dominant pattern.4


In 1998 inactivating germline mutations in the E-cadherin gene CDH1 were identified in three Maori families with diffuse gastric cancer.5 The CDH1 mutations in these families had an autosomal dominant pattern with high, but not complete, penetrance. Clinically apparent gastric cancer occurred at a young age with the youngest affected individual dying at the age of 14.5 Germline mutations of CDH1 have been detected in 30% to 50% of all patients with HDGC.3,6 More than 50 mutations have been seen across diverse ethnic backgrounds including all nationalities.3 In addition to gastric cancer, patients with germline CDH1 mutations have an increased risk of lobular breast cancer and this may present clinically prior to the diagnosis of gastric cancer in some individuals.7 CDH1 is the only gene that has been found to be present in HDGC. Approximately 70% to 80% of individuals with a germline CDH1 mutation develop diffuse gastric cancer, but this number may be even higher.8

CDH1 is located on chromosome 16q22.1 and encodes the calcium-dependent cell adhesion glycoprotein E-cadherin. Functionally, E-cadherin impacts maintenance of normal tissue morphology and cellular differentiation. CDH1 acts as a tumor suppressor gene in HDGC, with loss of function leading to loss of cell adhesion and subsequently to proliferation, invasion, and metastasis. The germline CDH1 mutation is a truncating mutation. Missense mutations have been reported but their functional significance is unknown. In vitro assays for cellular invasion and aggregation may predict the functional impact of missense mutations.6 Within the gastric mucosa, a ...

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