Gastric Cancer, Diffuse - CDH1

Clinical Features

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited susceptibility for diffuse gastric cancer signet ring carcinoma. Diffuse gastric cancer is caused by germline mutations in theCDH1 gene. The tumor infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without the ulcera typically associated with intestinal gastric cancer. The average age of onset in individuals with CDH1 mutations is 38 years within a range of 14-69 years. Men have a 67% estimated cumulative risk for gastric cancer by the age of 80 years, women 83%. Women also have a 60% risk of developing lobular breast cancer.

Families fulfilling the criteria of indication, the detection rate for CDH1 mutations is 25-50%. Hence, CDH1 mutations are not the only cause of hereditary diffuse gastric cancer. Referral to prophylactic gastrectomia is expressed from the age of 20 years onwards.

A pathological biopsy (gastroscopy once a year, 30 biopsies) in mutation free families presenting with gastric cancer is an indication for a gastrectomia.

Familial gastric cancer can be associated with the following three entities:

Hereditary diffuse gastric cancer (HDGC) with germline mutation in CDH1-gene
Hereditary nonpolyposis colorectal cancer (HNPCC) families caused by a germline mutation in a mismatch repair gene and associated microsatellite instability. The risk of gastric cancer in HNPCC is believed to be 10-15%.
Families with an accumulation of gastric cancer (intestinal type) and no microsatellite instability seem to make up the majority of hereditary gastric cancer. A disease causing gene mutation has not yet been identified.

Gastric cancer is seen in several other cancer predisposing syndromes, like Peutz-Jeghers (PJS), familial adenomatous polyposis (FAP) and Li-Fraumeni syndrome (LFS).

Revised criteria for consideration of CDH1 molecular testing were proposed by Brooks-Wilson et al. (2004):

Two or more cases of gastric cancer in the family, with at least one diffuse gastric cancer diagnosed before 50 years of age
Three or more cases of gastric cancer in the family, diagnosed at any age, with at least one documented case of diffuse gastric cancer
An individual diagnosed with diffuse gastric cancer before 45 years of age
An individual diagnosed with both diffuse gastric cancer and lobular breast cancer
One family member diagnosed with diffuse gastric cancer and another with lobular breast cancer
One family member diagnosed with diffuse gastric cancer and another with signet ring colon cancer

Genetic Information

The CDH1 gene is located on chromosome 16 (16q22.1) and encodes 16 exons. The activity of E-cadherin in cell adhesion is dependent upon its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-)