Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations

N Engl J Med. 2001 Jun 21;344(25):1904-9. doi: 10.1056/NEJM200106213442504.


Background: Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance, predominantly in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer.

Methods: Mutation-specific predictive genetic testing was performed by polymerase-chain-reaction amplification, followed by restriction-enzyme digestion and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopical analysis.

Results: Superficial infiltrates of malignant signet-ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were present in 65 of the 140 tissue blocks analyzed, representing in aggregate less than 2 percent of the gastric mucosa.

Conclusions: We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.

Publication types

  • Case Reports

MeSH terms

  • Adenocarcinoma / genetics*
  • Adult
  • Age of Onset
  • Cadherins / genetics*
  • Carcinoma, Signet Ring Cell / genetics
  • Female
  • Gastrectomy
  • Genetic Counseling
  • Genetic Testing
  • Germ-Line Mutation*
  • Humans
  • Male
  • Pedigree
  • Primary Prevention
  • Stomach / pathology
  • Stomach Neoplasms / diagnosis
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / prevention & control
  • Stomach Neoplasms / surgery


  • Cadherins