Analysis across multiple tumor types provides no evidence that mutant p53 exerts dominant negative activity

Abstract

Missense mutations in the TP53-binding domain predominate, and >30% of these occur in just eight codons. Dominant negative properties of mutant p53, taken together with the mutation susceptibility of the nucleotides in the codon, are believed to explain the prevalence of specific mutations, including hot spots. We analyzed multiple tumor types and found no difference in clinical characteristics or survival between patients with dominant negative p53 mutant tumors and those with TP53 mutations that are predicted to be non-dominant negative. The rate tumors underwent loss of heterozygosity in these respective mutation classes was nearly identical, suggesting that presence of stable, mutant protein with predicted dominant negative activity does not reduce selective pressure to inactivate the wild-type allele. Our data suggest all inactivating mutations of TP53 are equal, and the frequency of dominant negative, hot spot mutations is likely driven more by the relative mutability of the DNA at specific codons.