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p53 in Li Fraumeni syndrome










Varley JM (2003) Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat 21: 313-320. -> download the manuscript + its add

Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer. LFS is remarkable for the wide variety of cancer types involved, the young age at onset of malignancies, and the potential for multiple primary sites of cancer during the lifetime of affected individuals.

The following 3 criteria must be met for a diagnosis of familial LFS:

  1. A proband diagnosed with sarcoma when younger than 45 years
  2. A first-degree relative with any cancer diagnosed when younger than 45 years
  3. Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age

Most hereditary family cancer syndromes involve 1 or 2 specific tumor types, whereas members of LFS kindreds are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma. Several other cancers have been seen at lower rates in LFS kindreds.

The lifetime risk for cancer is estimated to be 85-90% for p53 mutation carriers.

Individuals who do not meet the classis criteria may meet Li-Fraumeni-Like (LFL) criteria as defined by Birch

  1. A proband with childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor <45 years
  2. A 1st or 2nd degree relative with typical LFS cancer at any age
  3. A 1st or 2nd degree relative with any cancer <60 years)

Greater than 50% of individuals clinically diagnosed with LFS have a germline mutation in p53. DNA sequence analysis of the entire coding region and splice sites of p53 can detect approximately 95% of those mutations. Since LFS is an autosomal dominant cancer predisposition syndrome, each child of an individual affected with LFS has a 50% (or 1 in 2) chance of inheriting the disease-causing mutation. De novo germline mutations have been reported in p53 but are rare.

Recently, heterozygous germline mutations in Chk2 have been identified in a subset of patients with Li-Fraumeni like syndrome. Chk2 (Checkpoint kinase 2) is a DNA damage-activated protein kinase that lies downstream of ATM in this pathway. It is essential for the activation of p53 after DNA damage.

More information on LFS can be found at the folowing web sites

OMIM -> Go to OMIM
Geneclinic -> Go to geneclinic

p53 Mutation in a Li-Fraumeni family. In normal cells, both the normal and the mutant allele can be found. In tumor, wild type p53 allele can be lost.


Germline ChK2 mutation in a LFS family

Spectrum of p53 mutations in Li-Fraumeni families




Meta-analysis of p53 loss of function in Li-Fraumeni family
Points ; mean p53 activity as measured by transactivation with the WAF1promoter ; bars , 95 % CI. The mean and 95 % CI of p53 activity for all studies combined for a specific type of cancer is shown on the far left of each graph.
Horizontal line, mean of the combined studies. The publication code is indicated on the x-axis : the first number is an anonymous ID for the publication and the second number indicates the number of p53 mutants included in this study. Studies are presented from left to right in decreasing order of number of p53 mutants. The y-axis corresponds to p53 transactivation activity, with a value of 1.5 for the negative control and a value of 2.5 for 100 % of wild-type activity. Only studies with 5 or more p53 mutations are shown on the graph.

More information about this statistical analysis can be found in this article:

Soussi, T., Asselain, B., Hamroun, D., Kato, S., Ishioka, C., Claustres, M. and Beroud, C. (2006) Meta-analysis of the p53 mutation database for mutant p53 biological activity reveals a methodologic bias in mutation detection. Clin Cancer Res, 12, 62-69. Download the pdf


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