P53 In Human Cancers

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P53 is mutated in some 50% of human tumors (see http://perso.curie.fr/Thierry. Soussi,www.iarc.fr/p53/index.html and http://cancergenetics.org/p53.htm, 2,3,7). There are about 18,000 such entries in existing databases, the vast majority ofwhich are missense mutations that apparently disable p53 tumor suppressor function. Table 1 lists the various mechanisms involved in p53 inactivation. While DNA sequence alterations (missense mutations, deletions and insertions, abnormal splicing) are more common in some malignancies compared to others, the other mechanisms shown in Table 1

Table 1. The various ways P53 may be inactivated in malignancies, modified from (3)

Mechanism ofp53 in activation

Consequences of in activation

Missense mutations in the DNA-bi riding domain Carboxy-terminus deletions MDM2 gene amplification ARF deletion

Infection by some DNA viruses Failure of p53 to localize to the nucleus

Failure of p53 as a transcription factor No p53 tt'lramers are formed Enhanced p53 proteolysis Impaired inhibition of MDM2 Viral products inactivate p53 or increase its degradation p53 does not function are limited to narrow classes of tumors. Some mechanisms e.g human papilloma virus in cervical cancer, may be related to environmental access of the carcinogen, whereas others may reflect the specific differentiated tissue environment e.g. MDM2 amplification in sarcomas and brain tumors (3). Not all potential mechanisms for inactivation of the p53 pathways have been systematically investigated for the majority of tumors.

Not only do P53 and Rb pathways cross but also the products of some DNA viruses inactivate them both (1-3).

Of the almost 18,000 p53 mutations in human malignancies, 97% are clustered in the core of the DNA-binding domain and 75% represent missense mutations. Until quite recently only a limited number of the tumor-derived missense mutations have been shown to render p53 defective. In order to address this deficiency Kato et al (7) mutated all 393 residues for all possible substitutions, examined the transactivating capacity of the products, after appropriate editing. Overall, 36% of the mutants were functionally inactive and 64% of core domain mutants fell in that category. Except for mutants at the C-terminal tetramerization domain, the functional part of p53 was concentrated between residues 96 and 286. Even within the DNA-binding core, the secondary structures were more susceptible than the connecting loops to functional disruption. By the same token, the conserved regions in closer proximity to DNA were more sensitive to mutations than conserved region not as intimately associated with DNA. At least for some substitutions, there appear to be differential effect on the transactivation of the p53 responsive genes examined (MDM2, BAX, 14-3-3a, p53A1P1, GADD 45, Noxa, p53R2).

Interestingly, of the1266 (54.7%) mutants which could be explained by function/mutation notion, 39.1% were inactive for all 8 promoters and have never been reported in tumors, 15.6% were inactive and reported in tumors, 16.1% were reported at least once in tumors but retained wild type transactivating capacity, 1.6% were inactivating mutations but have never been reported in tumors (7) probably because they occur in p53 domains not usually studied for mutations) and finally 27.5% were inactive for only a limited number of promoters. The last category of mutants may well have partial function in tumor suppression but may show pleomorphism in their range of activity against various downstream target genes (7)

P53 mutations in thyroid cancer

The prevalence of p53 mutations (14.3%) in thyroid carcinoma overall is much lower than in common cancers (2,26). Most studies have limited mutation screening to exons 5-8. Apparent mutation hot spots were located at residues 167, 183, 213, 248 and 273, mapping to the DNA-binding core of the p53 protein (2, 26,27). Viewed in the light of recent developments (7), it is apparent that the mutations reported at the caroxby terminal ofexon 8 and indeed a few within the DNA-binding core (27), do not influence the transactivating capacity of p53. Such functionally silent mutants may have been accidentally expanded during clonal selection of tumor cells. It cannot, however, be excluded that these apparently functionally silent mutants within the DNA-binding core may have minor disruptive influence on p53's tumor-suppressive function unrelated to its transactivating capacity. In this context, the claim that homozygozity for p53 proline 72 (a polymorphic Arg/Pro site) predisposes to anaplastic carcinoma (28) cannot be sustained. That the silent mutation rate of p53 in thyroid carcinomas was almost 120 fold that expected and 6 times the average rate of p53 silent mutations in the databases, the apparent random distribution of these mutations and distribution of multiple mutations (doublets, triplets) in accordance with Poisson's expectations suggest that p53 is particularly hypermutable in malignant thyroid tumors (2,27).

Almost a third of the mutations in p53 comprise G: C—>A: T transitions at CpG dinucleotides and 5 of 6 mutation hotspots (codons 175, 245, 273 and 282) are CpG sites. mC (5-methylcystosirie) is frequently converted to T by spontaneous hydrolytic deamination, forming a basis for an epigenetic mutational mechanism. These epige-netic events occur predominantly in poorly differentiated and anaplastic tumors; with one exception each all transitions at codons 273 and 248 were found in such tumors (2). Although the distribution of C—>T/G—>-A transitions suggest that mC deamination is as likely to be time-dependent as replication- dependent (29), we speculate that it may occur at the thyroidal stem cell stage.

Even though p53 is only one of many pathways leading to thyroid cancer it appears to have a pivotal role in differentiated thyroid function, in that thyroid -specific differentiation genes are re-expressed on anaplastic thyroid cancer cells harbouring p53 mutant with transfection of wild type p53 (30).

Mutations in radiation related thyroid cancer

The prevalence of p53 mutations thyroid cancers related to radiation is no different from that in the non-irradiated tumor population (2,27). However, the frequency distribution of the mutation spectrum is radically different between two groups (Table 2). Moreover, the radiation—related thyroid tumors show higher G: C—s>-A: T transitions rates and silent mutations than the non-radiation related thyroid tumors. Experimental radiation of thyroid epithelial cells was found to increase the rate ofp53 silent mutations (31). The role of radiation in targeting mutation sites is further bolstered by the fact that none of the mutations in radiation related tumors involved CpG dinucleotides as opposed to one-quarter in the non-radiation related tumors.

Table 2, Mutation spectrum in radiation-related compared to non-radiation related thyroid carcinomas

P53 codons


Non-radiation related

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