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Genetic Mutations in Hereditary Diffuse Gastric Cancer

Germline mutations in the CDH1 gene can be detected in up to 50% of families with hereditary diffuse gastric cancer.

Hereditary diffuse gastric cancer is an autosomal dominant disorder that is associated with a variety of different mutations in the epithelial cadherin (CDH1) gene. Affected families have high rates of this cancer (occurring as early as the second decade of life) and an increased risk for lobular breast cancer. Penetrance of CDH1 appears to be greater in women than in men. To determine whether recurring germline CDH1 mutations result from a common ancestry or from unique independent mutations, investigators studied 38 families who met the diagnostic criteria for hereditary diffuse gastric cancer.

Genetic sequencing identified 13 mutations (6 of which were novel) in 15 families, for a detection rate of 40%. Haplotype testing results were available for seven of these families and were compared with results from seven previously studied families. Four families, all from Newfoundland, were found to have a common mutation and a common haplotype, suggesting a founder effect.

The authors conclude that a germline mutation in the CDH1 gene can be identified in 40% of families with a history of gastric cancer and in 50% of families with two cases of diffuse gastric cancer diagnosed before age 50. They also suggest that a common mutation and haplotype might be responsible for the high incidence of gastric cancer seen in Newfoundland.

Comment: This highly detailed paper provides important information about families affected by hereditary diffuse gastric cancer. As with other genetic cancer syndromes, detecting a specific germline mutation in a patient who meets clinical criteria for the syndrome allows other family members to be tested for the mutation. Those with the same genotype can be targeted for aggressive surveillance and even potential prophylactic gastrectomy. Unfortunately, only 40% to 50% of families that meet clinical criteria for hereditary diffuse gastric cancer have a mutation in the CDH1 gene, and those families carry a variety of different independent mutations. Members of potentially affected families without CDH1 mutations are therefore left uncertain about their risk for cancer and the necessity for aggressive surveillance and preventive interventions.

— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)

Published in Journal Watch Gastroenterology June 5, 2007

Citation(s):

Kaurah P et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007 Jun 6; 297:2360-72.

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• Medline abstract (Free)

Kangelaris KN and Gruber SB. Clinical implications of founder and recurrent CDH1 mutations in hereditary diffuse gastric cancer. JAMA 2007 Jun 6; 297:2410-1.

• Original article (Subscription may be required)
• Medline abstract (Free)