p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma.
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.
Ushiku
Tetsuo
T
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Chong
Ja-Mun
JM
Uozaki
Hiroshi
H
Hino
Rumi
R
Chang
Moon-Sung
MS
Sudo
Makoto
M
Rani
Barua Rita
BR
Sakuma
Kazuya
K
Nagai
Hideo
H
Fukayama
Masashi
M
D001483:Base Sequence; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D005260:Female; D005756:Gastritis / Q000473:pathology / Q000821:virology; D015967:Gene Expression Regulation, Viral; D016481:Helicobacter Infections / Q000235:genetics / Q000473:pathology / Q000821:virology; D016480:Helicobacter pylori / Q000302:isolation & purification; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013270:Stomach / Q000473:pathology / Q000821:virology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins