1. ¹Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
2. ²Department of Pathology, University of Virginia Health System, Charlottesville, Virginia
3. ³Istituto Policattedva di Scienze Chirurgiche, Universita' Degli Studi di Siena, Via della Scotte, Siena, Italy
4. ⁴Istituto di Anatomia Eistologia Patologica, Universita' Degli Studi di Siena, Via della Scotte, Siena, Italy
5. ⁵Henry Ford Hospital, Detroit, Michigan

Correspondence: Steven M. Powell, M.D., Department of Medicine, Division of Gastroenterology/Hepatology, University of Virginia, Health Sciences Center, Box 800708, Charlottesville, VA 22908-0708; e-mail: smp8n@virginia.edu; fax: (804)-243-0491.

Accepted 25 May 2001.

Abstract

Loss of the cell adhesion molecule E-cadherin has been observed in a variety of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer. We sought to determine the prevalence and nature of E-cadherin alterations in "sporadic" gastric carcinomas. We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expression determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 diffuse-type cancers harbored genetic alterations in the E-cadherin gene. Novel mutations predicted to significantly compromise protein function were found within 4 of these cancers, 2 of which harbored alterations resulting in biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous abnormality. Notably, one germline E-cadherin mutation was also identified within these "sporadic" diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohistochemistry revealed aberrant or negative protein expression in seven diffuse-type tumors, four of which correlated with the genetic alterations. Both diffuse and intestinal-type tumors exhibited low rates of LOH, suggesting that allelic loss at the locus is not a common mechanism for E-cadherin inactivation during gastric tumorigenesis. Our observations suggest that inactivation of the E-cadherin gene occurs only in a subset of diffuse-type gastric cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, although rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications