The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.

转录因子 p53 在细胞防御癌症发展中起关键作用。它几乎在每个肿瘤中都失活，而在第二个肿瘤中，这种失活是由于 TP53 基因突变造成的。从这个角度来看，我们表明这种多样化的突变谱在所有其他癌症相关蛋白中是独一无二的，并讨论了是什么驱动了癌症中 TP53 突变的选择。我们强调有几个因素共同使 p53 蛋白特别容易受到不断困扰我们基因组的突变的失活。TP53 基因似乎已成为其自身进化历史的受害者，该进化历史将其结构和功能塑造为多能肿瘤抑制因子，但其 DNA 结合域的结构脆弱性增加。TP53 功能丧失 - 具有相关的显性负面影响 - 是损害 TP53 肿瘤抑制功能的主要机制，无论新形态表型是否与其中一些变体相关。