Prophylactic total gastrectomy in hereditary diffuse gastric cancer: identification of two novel CDH1 gene mutations-a clinical observational study.

Inactivating mutations in the CDH1 (E-cadherin) gene are the predisposing cause of gastric cancer in most families with hereditary diffuse gastric cancer (HDGC). The lifetime risk of cancer in mutation positive members is more than 80 % and prophylactic total gastrectomy is recommended. Not all mutations in the CDH1 gene are however pathogenic and it is important to classify mutations before this major operation is performed. Probands from two Danish families with gastric cancer and a history suggesting HDGC were screened for CDH1 gene mutations. Two novel CDH1 gene mutations were identified and found pathogenic. In silico and mini-gene assay were used to predict the functional consequence in one of them. Mutation carriers were offered endoscopy and total gastrectomy. The gastric specimens were completely sectioned and examined histologically. Seven asymptomatic mutation carriers were operated. Hospital stay was 6-8 days and there were no complications. Small foci of diffuse gastric cancer were found in all patients-intramucosal in six and advanced in one. Preoperative endoscopic biopsies had revealed a microscopic cancer focus in two of the patients. Our data confirmed the pathogenic nature of both mutations and strongly support the recommendation of total gastrectomy in asymptomatic CDH1 gene mutation carriers. The functional consequences of novel CDH1 gene mutations with uncertain effects should be tested before correct advice and treatment can be given.