Thyroid carcinoma is characterized by genomic instability: evidence from p53 mutations.
p53 is a transcription factor with multifaceted regulatory functions in cell cycle progression, DNA repair, and programmed cell death. Inactivating mutations have been described in 50% of human cancers. These mutations appear to be important in tumor progression and response to chemotherapy and radiation treatment and thus clinical outcome. p53 mutations are found in 14% of malignant thyroid tumors and are more frequent in poorly differentiated and anaplastic tumors. Given that p53 is a late event in the notional multistep pathogenesis of cancer, we examined its mutation rates as a measure of genomic instability (hypermutability) of malignant thyroid tumors and also wondered whether radiation enhances that proclivity to genomic instability. To that end we have extracted all available data from the p53 mutation database (http://www.perso@curie.fr), verified, extended, where applicable, and supplemented that information from published reports. We were able to identify 100 entries. The distribution of the p53 mutational events--deletions/insertions, transitions versus transversion mutations--was similar to that of the database as a whole. The silent mutation rate of 17.8%, not different from the expected 25%, is consistent with a random occurrence of these mutations. The silent mutation rate is 120 times that expected and is 6 times that of the database. Moreover, the distribution of p53 mutations is compatible with Poisson's distribution, which taken with silent mutation rates indicates that p53 is particularly hypermutable in thyroid carcinomas. Epigenetic deamination of CpG dinucleotide at highly oncogenic DNA-contact residues is a feature of poorly differentiated tumors and thus associated with tumor progression. The rates of p53 mutations (15.4%) in radiation-related cancers were very similar to those in apparently spontaneously arising tumors, although there was a highly significant heterogeneity (P < 0.0005) in the residues mutated. None involved CpG deamination. It is apparent that thyroid cancer exhibits remarkable genomic instability evidenced by p53 hypermutability. Spontaneous epigenetic mutational events are involved in tumor progression and while radiation increases the absolute prevalence of thyroid cancer in the susceptible it does not increase the rate of p53 mutation and seemingly targets different non-DNA-contact residues than those in spontaneously arising tumors.