TY - JOUR
T1 - Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer
AU - Ascão, Jennifer J.
AU - Frierson, Henry
AU - Moskaluk, Christopher A.
AU - Harper, Jeffrey C.
AU - Roviello, Franco
AU - Jackson, Charles E.
AU - El-Rifai, Wa'el
AU - Vindigni, Carla
AU - Tosi, Piero
AU - Powell, Steven M.
N1 - Funding Information:
Copyright © 2001 by The United States and Canadian Academy of Pathology, Inc. VOL. 14, NO. 10, P. 942, 2001 Printed in the U.S.A. Date of acceptance: May 25, 2001. This work was supported by the R. Robert and Sally D. Funderburg Research Scholar Award in Gastric Biology related to cancer through the American Digestive Health Foundation and by NCI grant R01 (CA67900–06). Address reprint requests to: 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: [email protected]; fax: (804)-243-0491.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Diffuse-type gastric cancer
KW - E-cadherin
KW - LOH
KW - Sporadic gastric cancer
UR - http://www.scopus.com/inward/record.url?scp=17944375244&partnerID=8YFLogxK
U2 - 10.1038/modpathol.3880416
DO - 10.1038/modpathol.3880416
M3 - Article
C2 - 11598162
AN - SCOPUS:17944375244
SN - 0893-3952
VL - 14
SP - 942
EP - 949
JO - Modern Pathology
JF - Modern Pathology
IS - 10
ER -