Hypermethylation-associated transcriptional silencing of E-cadherin in primary sporadic colorectal carcinomas

J Pathol. 2002 Dec;198(4):442-9. doi: 10.1002/path.1237.

Abstract

Loss of E (epithelial)-cadherin expression has been previously documented in sporadic colorectal carcinomas (SCRCs), but not as a consequence of mutations or allelic loss. In this study, the methylation status of the E-cadherin promoter was examined by utilizing the methylation-specific polymerase chain reaction (MSP) assay in 63 primary SCRCs and paired adjacent normal tissues. This was correlated with E-cadherin expression at both the RNA and the protein levels using multiplex reverse transcription (RT)-PCR and immunohistochemistry (IHC), respectively. Data were associated with the patients' clinicopathological features. Methylated alleles were present in 34/61 (56%) of the samples examined. Decreased E-cadherin mRNA expression was demonstrated in 29/61 carcinomas (47.5%) and was significantly associated with lymph node (LN) metastases (p = 0.03, Kruskal-Wallis) and tumour stages Astler-Coller B1 and B2 (p = 0.01, chi(2)). E-cadherin IHC expression was significantly associated with the absence of LN metastases (p = 0.01, chi(2)) and tumour stages Astler-Coller B1 and B2 (p = 0.002, Kruskal-Wallis) in 28/63 (44.4%) of the samples examined. Twenty-three out of 29 (79.3%) samples with decreased mRNA expression and 20/33 (60.6%) with detected protein expression revealed methylated (p = 0.03, Kruskal-Wallis) and unmethylated (p = 0.01, Kruskal-Wallis) alleles, respectively. In agreement with previous work demonstrating that somatic mutations and loss of heterozygosity of the E-cadherin gene are rare or absent in the majority of SCRCs studied so far, this study reports a consistent and uniform decrease or absence of E-cadherin expression, associated with aberrant methylation, in the majority of carcinomas examined, suggesting an epigenetically mediated loss of E-cadherin function in these carcinomas.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • DNA Methylation*
  • Female
  • Gene Silencing*
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Polymerase Chain Reaction / methods
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic

Substances

  • Cadherins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm