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

Background: Germ-line truncating mutations in the E-cadherin (CDH1) gene ha ve been found in families with hereditary diffuse gastric cancer. These fam ilies are characterized by a highly penetrant susceptibility to diffuse gas tric cancer with an autosomal dominant pattern of inheritance, predominantl y in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 f rom two unrelated families with hereditary diffuse gastric cancer. Methods: Mutation-specific predictive genetic testing was performed by poly merase-chain-reaction amplification, followed by restriction-enzyme digesti on and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mut ations who were between 22 and 40 years old. In each case, the entire mucos a of the stomach was extensively sampled for microscopical analysis. Results: Superficial infiltrates of malignant signet-ring cells were identi fied in the surgical samples from all five persons who underwent gastrectom y. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were p resent in 65 of the 140 tissue blocks analyzed, representing in aggregate l ess than 2 percent of the gastric mucosa. Conclusions: We recommend genetic counseling and consideration of prophylac tic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH 1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer. (N Engl J Med 2001;344:1904-9.) Copyright (C) 2001 Massach usetts Medical Society.