Why are there hotspot mutations in the TP53 gene in human cancers?

Abstract

The p53 gene contains homozygous mutations in ~50-60% of human cancers. About 90% of these mutations encode missense mutant proteins that span ~190 different codons localized in the DNA-binding domain of the gene and protein. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates the p53 transcriptional pathway. Eight of these mutations are localized in codons that account for ~28% of the total p53 mutations and these alleles appear to be selected for preferentially in human cancers of many tissue types. This article explores the question 'Why are there hotspot mutations in the p53 gene in human cancers?' Four possible reasons for this are considered; (1) the hotspot mutant alleles produce a protein that has a highly altered structure, (2) environmental mutagens produce allele-specific changes in the p53 gene, (3) these mutations arise at selected sites in the gene due to a specific DNA sequence, such as a methylated cytosine residue in a CpG dinucleotide, which has a higher mutation rate changing C to T nucleotides, (4) along with the observed change in mutant p53 proteins, which produce a loss of function (DNA binding and transcription), some mutant proteins have an allele-specific gain of function that promotes cancer. Evidence is presented that demonstrates the first three possibilities all contribute some property to this list of hotspot mutations. The fourth possibility remains to be tested.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Most hotspot residues are near the TP53 DNA-binding interface: Several 'hotspot' residues that are frequently mutated in human cancers make contact with DNA (PDB code 1TUP, chain B). (a) R248 and R273 make direct contacts with DNA, whereas several other 'hotspot' residues are located near this interface (R249, R282). (b) Other frequently mutated positions occur far from the DNA-binding interface, such as Y220. (c) The Zinc binding site is close to the DNA-binding interface and coordinated by a loop containing R175

Figure 2

Most mutations in the TP53 DNA-binding domain appear neutral-like: the distribution of VIPUR scores is skewed toward neutral (<0.5) scores, suggesting that many mutations in TP53 are more wildtype-like

Figure 3

'Hotspot' mutations are mostly deleterious: Mutations occurring at designated 'hotspot' residues are commonly found in tumors and two-thirds of these mutants achieve highly deleterious scores in VIPUR. Eight positions were considered hotspots, with 46 mutations accessible from a single-nucleotide change to the TP53 DNA sequence. VIPUR suggests that most of these mutations above 0.7 score will be highly damaging to TP53 function

Figure 4

VIPUR deleterious scores correlate with COSMIC Counts but do not explain the outliers: A significant positive correlation exists between VIPUR scores and tumor prevalence in the COSMIC database (r=0.41, P-value∼0, Pearson correlation with log10 COSMIC counts). Although most mutations in TP53 can be described using VIPUR as structural loss of function mutations, many mutations occur much more commonly than would be expected. Curiously, the 10 most common mutations are distributed over the entire VIPUR score range. Although frequently occurring mutations with high VIPUR scores may simply be more damaging, the frequency of mutations with neutral scores (<0.5) is not explained by VIPUR. The prevalence of these mutations may be explained by other factors