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

Jennifer J. Ascão, Henry Frierson, Christopher A. Moskaluk, Jeffrey C. Harper, Franco Roviello, Charles E. Jackson, Wa'el El-Rifai, Carla Vindigni, Piero Tosi, Steven M. Powell

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)942-949
Number of pages8
JournalModern Pathology
Volume14
Issue number10
DOIs
StatePublished - Oct 29 2001
Externally publishedYes

Keywords

  • Diffuse-type gastric cancer
  • E-cadherin
  • LOH
  • Sporadic gastric cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Ascão, J. J., Frierson, H., Moskaluk, C. A., Harper, J. C., Roviello, F., Jackson, C. E., El-Rifai, W., Vindigni, C., Tosi, P., & Powell, S. M. (2001). Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer. Modern Pathology, 14(10), 942-949. https://doi.org/10.1038/modpathol.3880416