p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma

Int J Cancer. 2007 Jan 1;120(1):60-6. doi: 10.1002/ijc.22275.

Abstract

To clarify the significance of p73 in Epstein-Barr virus (EBV)-associated gastric carcinoma (GC), the immunohistochemical expression and CpG-island methylation of p73 were evaluated in cancer tissues and adjacent nonneoplastic tissues of GC with and without EBV infection. Loss of p73 expression by immunohistochemistry was specific to EBV-associated GC (11/13) compared to EBV-negative GC (3/38), which was independent of abnormal p53 expression. With methylation-specific polymerase chain reaction (MSP), the aberrant methylation of p73 exon 1 was similarly specific to EBV-associated GC (12/13), and also rare in EBV-negative GC (2/38). Bisulfite sequencing for p73 exon 1 and its 5' region confirmed the MSP results, showing uniform and high-density methylation in EBV-associated GC. Comparative MSP analysis of p14, p16 and p73 methylation, using 20 cases each of formalin-fixed and paraffin-embedded tissues of early GC with and without EBV infection, confirmed 2 types of methylation: global methylation with increased rates (p14 and p16) and specific methylation of p73 in EBV-associated GC. In nonneoplastic mucosa, p14, p16 and p73 methylation occurred in both EBV-associated (8/33, 6/34 and 3/38, respectively) and EBV-negative GC (6/23, 4/35, and 1/35). p73 methylation was observed in the mucosa without H. pylori infection in all 4 samples. Loss of p73 expression through aberrant methylation of the p73 promoter occurs specifically in EBV-associated GC, together with the global methylation of p14 and p16. A specific type of gastritis, prone to a higher grade of atrophy and p73 methylation, may facilitate the development of EBV-associated GC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Case-Control Studies
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Methylation*
  • DNA-Binding Proteins / genetics*
  • Epstein-Barr Virus Infections / genetics*
  • Epstein-Barr Virus Infections / pathology
  • Epstein-Barr Virus Infections / virology
  • Female
  • Gastritis / pathology
  • Gastritis / virology
  • Gene Expression Regulation, Viral*
  • Helicobacter Infections / genetics
  • Helicobacter Infections / pathology
  • Helicobacter Infections / virology
  • Helicobacter pylori / isolation & purification
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / isolation & purification*
  • Humans
  • Male
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • Polymerase Chain Reaction
  • Stomach / pathology
  • Stomach / virology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / virology*
  • Tumor Protein p73
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics*

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Nuclear Proteins
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins