Hypermethylation-associated Inactivation of p14 Is Independent of p16 Methylation and p53 Mutational Status

نویسندگان

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

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

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تاریخ انتشار 2000