p53 mutation and cancer
p53 MUTATIONS IN COLORECTAL CANCER
Iacopetta, B. (2003) TP53 mutation in colorectal cancer. Hum Mutat, 21, 271-276.-> Download
p53 mutations have been described in about 40% to 50 % of colorectal carcinomas. LOH of the short arm of chromosome 17 is also found in most of these tumors and are associated with aggressive tumors. Analysis of colorectal adenomas shows that the p53 mutation is rare in such tumors. Studies at various tumor stages in colorectal carcinomas demonstrated that p53 mutations are generally a late event which is followed by loss of the remaining wild type allele. In a study of 274 colorectal tumors of 4 histopathological grades, Kikuchi-Yanoshita, et al.showed that the p53 mutation and LOH of the 17p chromosome were found more frequently in carcinomas than in early adenomas in both familial and non-familial adenomatous polyposis patients. All these data suggest that p53 alterations are associated with the conversion from colorectal adenoma to early carcinoma.
Analysis of the mutational event leading to p53 gene mutations in this carcinoma indicates that 80% of the mutations are GC->AT transitions which are predominantly located at the CpG dinucleotide thus suggesting that most of the mutations that alter the p53 gene in this cancer are due to endogenous processes related to the deamination of 5-methylcytosine . In fact, the three hot spot codons 175, 248 and 273 contain such a dinucleotide. More than 90 % of the mutational events in these codons are compatible with a deamination phenomenon. This observation is confirmed by various studies showing that codons 175, 248 and 273 are methylated in vivo. On the other hand, GC-> TA transversions, deletions, insertions or splice mutations are a very rare event.
This high frequency of mutation at CpG dinucleotide in colon cancer leads to a very important concentration of mutations in a very few number of codon (see figures below).
Spectrum of p53 mutations in colon cancer