title: High-density methylation of p14ARF and p16INK4A in Epstein-Barr virus-associated gastric carcinoma.
abstract: Promoter hypermethylation of various tumor-related genes is extremely frequent in gastric carcinoma (GC) associated with Epstein-Barr virus (EBV). To investigate the significance of the promoter methylation in this type of GC, we examined the methylation densities of the promoter regions of p14ARF and p16INK4A in EBV-associated (n=7) and EBV-negative (n=14) GC. Bisulfite sequencing demonstrated a high frequency of concurrent methylation of p14ARF and p16INK4A promoter regions in EBVaGC. Methylation was observed in all 29 CpG sites of p14ARF and all 16 sites of p16INK4A with equally high densities. In EBV-negative GC, the methylation profiles differed between the 2 genes. Promoter methylation was sporadic and variable in p14ARF, and only the last position of CpG in p14ARF was methylated at high frequency. High-density methylation in p16INK4A was observed in a subset of GC, but the first position of CpG was never methylated in EBV-negative GC. These findings suggest the presence of mechanisms of de novo and maintenance methylation specific to EBVaGC that might be associated with EBV infection.
authors.affiliation: Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sakuma
authors.forename: Ja-Mun
authors.initials: JM
authors.lastname: Chong
authors.forename: Makoto
authors.initials: M
authors.lastname: Sudo
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ushiku
authors.forename: Yoko
authors.initials: Y
authors.lastname: Inoue
authors.forename: Junji
authors.initials: J
authors.lastname: Shibahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uozaki
authors.forename: Hideo
authors.initials: H
authors.lastname: Nagai
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics* / Q000503:physiopathology / Q000821:virology*; D019175:DNA Methylation; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000821:virology*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
chemical_list: D025803:Tumor Suppressor Protein p14ARF