Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer

Loss of the cell adhesion molecule E-cadherin has been observed in a variet y of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer. We sought to determine t he prevalence and nature of E-cadherin alterations in "sporadic" gastric ca rcinomas. We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expressio n determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 d iffuse-type cancers harbored genetic alterations in the E-cadherin gene. No vel mutations predicted to significantly compromise protein function were f ound within 4 of these cancers, 2 of which harbored alterations resulting i n biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous ab normality. Notably, one germline E-cadherin mutation was also Identified wi thin these "sporadic" diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohisto chemistry revealed aberrant or negative protein expression in seven diffuse -type tumors, four of which correlated with the genetic alterations. Both d iffuse and Intestinal-type tumors exhibited low rates of LOH, suggesting th at allelic loss at the locus Is not a common mechanism for E-cadherin inact ivation during gastric tumorigenesis. Our observations suggest that inactiv ation of the E-cadherin gene occurs only in a subset of diffuse-type gastri c cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, althou gh rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications.