TP53 and cancer: All but 7 residues of the 393 amino acid residue p53 protein have been the target of at least 1 mutation in human cancer, and in the core domain that contains the DNA-binding region, each residue has been found to be mutated at least 5 times in independent tumors, and up to >2,000 times for hotspot mutants.19, 20 This vast scattering of TP53 mutations is due to the marked fragility of the core domain, which can be destabilized by amino acid substitutions at many different positions.21