P14 methylation in human colon cancer is associated with microsatellite instability and wild-type p53

Gastroenterology. 2003 Mar;124(3):626-33. doi: 10.1053/gast.2003.50102.


Background and aims: Colorectal cancers with high levels of microsatellite instability (MSI-H) have an unexplained low rate of p53 gene mutations. Most such cancers have the CpG island methylator phenotype (CIMP+) with methylation and transcriptional silencing of the mismatch repair gene MLH1. The p14 (ARF) gene on chromosome 9p is deleted and/or silenced by hypermethylation in a subset of human malignancies. There is evidence suggesting that p14 suppresses tumorigenicity by stabilizing the p53 protein.

Methods: We investigated the role of p14 in colorectal cancer by determining its methylation status in cancers that were studied previously for microsatellite instability, CIMP, and mutations of p53 and K-RAS.

Results: p14 methylation was present in 21 of 94 cases overall (22%) and was frequent particularly in the subgroups with MSI-H (52% [11 of 21] vs. 14% [10 of 72], P = 0.004), in CIMP+ cases (40% [19 of 48] vs. 4% [2 of 46], P < 0.001), and in cases without p53 alterations (36% [17 of 47] vs. 7% [3 of 44], P = 0.004). Of 91 fully characterized cases, 41 (45%) had p53 mutations alone, 17 (19%) had p14 methylation alone, 30 (33%) had neither, but only 3 (3%) had both p53 mutations and p14 methylation. p14 methylation is an early event in colorectal carcinogenesis, being detectable in normal aging epithelium by using sensitive assays.

Conclusions: In colorectal cancer, p14 methylation is associated with the presence of microsatellite instability and with absence of p53 mutations. The results provide a possible explanation for the paucity of p53 mutations in colon cancers with microsatellite instability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Cell Line
  • Colon / metabolism
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • DNA Methylation*
  • Female
  • Humans
  • Intestinal Mucosa / metabolism
  • Male
  • Microsatellite Repeats / genetics*
  • Tumor Suppressor Protein p14ARF / genetics*
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / genetics*


  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53