Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients

Hum Mutat. 2013 Mar;34(3):453-61. doi: 10.1002/humu.22254. Epub 2013 Feb 11.


In contrast to other tumor suppressor genes, the majority of TP53 alterations are missense mutations. We have previously reported that in the Li-Fraumeni syndrome (LFS), germline TP53 missense mutations are associated with an earlier age of tumor onset. In a larger series, we observed that mean age of tumor onset in patients harboring dominant negative missense mutations and clearly null mutations was 22.6 and 37.5 years, respectively. To assess the impact of heterozygous germline TP53 mutations in the genetic context of the patients, we developed a new functional assay of the p53 pathway on the basis of induction of DNA damage in Epstein-Barr-virus-immortalized lymphocytes, followed by comparative gene-expression profiling. In wild-type lymphocytes, we identified a core of 173 genes whose expression was induced more than twofold, of which 46 were known p53 target genes. In LFS lymphocytes with canonical missense mutations, the number of induced genes and the level of known p53 target genes induction were strongly reduced as compared with controls and LFS lymphocytes with null mutations. These results show that certain germline missense TP53 mutations, such as those with dominant negative effect, dramatically alter the response to DNA damage. This probably explains why TP53 alterations are predominantly missense mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Blotting, Western
  • Case-Control Studies
  • Child, Preschool
  • Computational Biology
  • DNA Damage
  • Female
  • Gene Expression Profiling
  • Gene Rearrangement
  • Genotype
  • Germ-Line Mutation*
  • Humans
  • Li-Fraumeni Syndrome / diagnosis*
  • Li-Fraumeni Syndrome / genetics*
  • Male
  • Microarray Analysis
  • Middle Aged
  • Mutation, Missense*
  • Sequence Analysis, RNA
  • Tumor Suppressor Protein p53 / genetics*


  • TP53 protein, human
  • Tumor Suppressor Protein p53