p53 database

p53 database

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p53 mutation and cancer

p53 MUTATIONS IN COLORECTAL CANCER

Iacopetta, B. (2003) TP53 mutation in colorectal cancer. Hum Mutat, 21, 271-276.-> Download

Colon cancer

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

DISTRIBUTION OF p53 MUTATIONS IN COLON CANCER

MUTATIONAL EVENTS IN COLON CANCER

Meta-analysis of p53 loss of function in Colorectal cancer. Points ; mean p53 activity as measured by transactivation with the WAF1promoter ; bars , 95 % CI. The mean and 95 % CI of p53 activity for all studies combined for a specific type of cancer is shown on the far left of each graph. Horizontal line, mean of the combined studies. The publication code is indicated on the x-axis : the first number is an anonymous ID for the publication and the second number indicates the number of p53 mutants included in this study. Studies are presented from left to right in decreasing order of number of p53 mutants. The y-axis corresponds to p53 transactivation activity, with a value of 1.5 for the negative control and a value of 2.5 for 100 % of wild-type activity. Only studies with 5 or more p53 mutations are shown on the graph. More information about this statistical analysis can be found in this article: Soussi, T., Asselain, B., Hamroun, D., Kato, S., Ishioka, C., Claustres, M. and Beroud, C. (2006) Meta-analysis of the p53 mutation database for mutant p53 biological activity reveals a methodologic bias in mutation detection. Clin Cancer Res, 12, 62-69. Download the pdf