Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status

Manel Esteller, Silvia Tortola, Minoru Toyota, Gabriel Capella, Miguel Angel Peinado, Stephen B. Baylin, James G. Herman

Research output: Contribution to journalArticlepeer-review


The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16(INK4a) and p14(ARF), which share an exon using different reading frames. p14(ARF) antagonizes MDM2-dependent p53 degradation. However, no point mutations in p14(ARF) not altering p16(INK4a) have been described in primary tumors. We report that p14(ARF) is epigenetically inactivated in several colorectal cell lines, and its expression is restored by treatment with demethylating agents. In primary clorectal carcinomas, p14(ARF) promoter hypermethylation was found in 31 of 110 (28%) of the tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in any normal tissues. p14(ARF) methylation appears in the context of an adjacent unmethylated p16(INK4a) promoter in 16 of 31 (52%) of the carcinomas methylated at p14(ARF). Although p14(ARF) hypermethylation was slightly overrepresented tumors with wild-type p53 compared to tumors harboring p53 mutations {19 of 55 (34%) versus 12 of 55 (22%)}, this difference did not reached statistical significance. p14(ARF) aberrant methylation was not related to the presence of K-ras mutations. Our results demonstrate that p14(ARF) promoter hypermethylation is frequent in colorectal cancer and occurs independently of the p16(INK4a) methylation status and only marginally in relation to the p53 mutational status.

Original languageEnglish (US)
Pages (from-to)129-133
Number of pages5
JournalCancer Research
Issue number1
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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