Alterations and hypermethylation of the p14(ARF) gene in gastric cancer

Int J Cancer. 2000 Sep 1;87(5):654-8. doi: 10.1002/1097-0215(20000901)87:5<654::aid-ijc6>;2-p.


p14(ARF), generated through an alternative splicing process that replaces the first exon, 1alpha, of p16(INK4a) with exon 1beta, located >15 kb upstream of exon 1alpha, has been shown to function as a growth suppressor. We examined 11 gastric cancer cell lines for mRNA expression, homozygous deletion, mutation, and promoter methylation of the p14(ARF) gene. No mRNA expression was detected in 5 of the 7 diffuse-type cell lines. All intestinal cell lines displayed normal levels of expression except for one with a low level of expression. Of the 5 cell lines without expression, 3 (MKN45, NUGC-2, and NUGC-4) and 1 (KATO III) displayed homozygous deletion and methylation of the p14(ARF) gene, respectively. No mutation was found in the whole coding region of the p14(ARF) gene in 8 cell lines without homozygous deletion. Our results indicate that the p14(ARF) gene is more frequently inactivated by homozygous deletion or methylation in diffuse-type gastric cancer cell lines (5/7, 71.4%) than in intestinal ones (0/4, P = 0.022). When we also analyzed 62 primary gastric cancers for the methylation status of the p14(ARF) promoter region, the methylation frequency tended to be higher in diffuse-type gastric cancers (15/33, 45.5%) than in intestinal ones (7/28, 25%). Thus, p14(ARF) alterations might be involved in diffuse-type gastric carcinogenesis.

Publication types

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

MeSH terms

  • Carrier Proteins / genetics
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Methylation*
  • Gene Deletion
  • Gene Expression
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Mutation
  • Promoter Regions, Genetic / physiology
  • Protein Biosynthesis
  • Proteins / genetics*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms / genetics*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics


  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53