Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome

Oncogene. 1998 Sep 3;17(9):1061-8. doi: 10.1038/sj.onc.1202033.


The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Chi-Square Distribution
  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Mutational Analysis
  • Family Health
  • Family*
  • Female
  • Genotype
  • Germ-Line Mutation / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Li-Fraumeni Syndrome / genetics*
  • Male
  • Middle Aged
  • Neoplasms / genetics*
  • Pedigree
  • Phenotype
  • Tumor Suppressor Protein p53 / genetics*


  • Tumor Suppressor Protein p53