P14 methylation in human colon cancer is associated with microsatellite instability and wild-type p53.
OBJECTIVE
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.
Shen
Lanlan
L
Department of Leukemia, The University of Texas at M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kondo
Yutaka
Y
Hamilton
Stanley R
SR
Rashid
Asif
A
Issa
Jean-Pierre J
JP
D000328:Adult; D000368:Aged; D002460:Cell Line; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53