p53 mutation and cancer
p53 MUTATIONS: ALL CANCER
Download a recent review:
Soussi T, Kato S, Levy PP, Ishioka C (2005) Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 25: 6-17. -> Download
Analysis of all point mutations in the p53 gene shows that 51% are G:C>A:T transitions, and 59% of these mutations affect a CpG dinucleotide. In mammalian cells, the cytosine in this dinucleotide is very often methylated and it has been shown that the 42 CpG sites of the p53 gene are methylated in normal tissue [Tornaletti & Pfeifer, 1995]. It is generally assumed that the higher deamination rate of 5-methylcytosine leading to a T/G mismatch that is not efficiently repaired could lead to this high rate of transversion in the p53 gene. Deamination of cytosine leads to a U/G mismatch that could be removed more efficiently. Although attractive, this hypothesis has not been formally demonstrated and several lines of evidence suggest that other models should also be investigated. Various studies have demonstrated that exogenous carcinogens, such as BPDE or UV sunlight, have a greater affinity for methylated CpG dinucleotides than their unmethylated counterparts [Denissenko et al., 1997; You et al., 1999 ]. It is conceivable that endogenous mutagens, derived from an altered cell metabolism, could also target methylated CpG dinucleotide leading to a high rate of transition.
The pattern of mutational events that inactivates the p53 gene is specific from one cancer to another. In colon cancer, there is a high rate of transitions at CpG dinucleotides, whereas in lung cancer, GC->TA transversion is the leading mutational event. These differences are due to the heterogeneity of the mutagenic process that inactivates p53 in these two cancers.
Alterations at codons 175, 248 and 273 correspond to 19% of all mutations described in the database and are usually considered to be hot spot mutations. However, these mutations must be interpreted very cautiously, as they present several levels of heterogeneity: i) several different variants are observed for each locus (Figure 1A and B); ii) the frequency of these variants differs from one cancer to another; and iii) some of these variants induce only a partial defect in biological properties. G-> T transversion is clearly different between the various cancers with a predominance in the two cancers related to tobacco smoking: lung cancer and head and neck cancer