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Genetic and Rare Diseases Information Center (GARD)

Other Names for this Disease
  • LFS1
  • Sarcoma family syndrome of Li and Fraumeni
  • SBLA syndrome (Sarcoma, Breast, Leukemia, and Adrenal Gland)
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Your Question

How does this syndrome begin in a lineage? Is the TP53 gene mutation a sudden and spontaneous mutation at conception? Does it have environmental causes? Is it a gradual generational erosion of gene integrity finally resulting in the full mutation that causes this syndrome? Are some TP53 genes mutated worse than others? We are trying to trace this through our family tree.

Our Answer

We have identified the following information that we hope you find helpful. If you still have questions, please contact us.

How is Li-Fraumeni syndrome inherited?

Li-Fraumeni syndrome is inherited in an autosomal dominant manner. This means that only one mutated copy of the disease-causing gene in each cell is sufficient to increase the risk of developing cancer. The mutated gene may be inherited from an affected parent or may occur for the first time in the affected individual (a de novo mutation). The proportion of individuals with a de novo mutation is unknown.[1] To our knowledge there is no evidence that environmental exposures increase a person's risk to be born with Li-Fraumeni syndrome.

Each child of an individual with an autosomal dominant condition has a 50% (1 in 2) chance to inherit the mutated gene. If the child of an affected parent does not inherit the mutated gene, that child cannot pass the mutated gene on to offspring.
Last updated: 8/8/2012

What causes Li-Fraumeni syndrome?

Li-Fraumeni syndrome is associated with mutations in the TP53 gene. More than 70% of individuals diagnosed clinically have an identifiable mutation in the TP53 gene.[1] TP53 is a tumor suppressor gene, which means that it normally helps to prevent too much cell growth, thus suppressing the development of cancer (in which cells grow too fast). Mutations in the TP53 gene can stop the gene from functioning properly, which allows cells to excessively divide and form tumors.[2]

A few families with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (a similar condition in which different patterns of specific cancers occur in affected family members) and no identifiable TP53 mutation were initially reported to have mutations in the CHEK2 gene. However, more recent analyses determined that CHEK2 is not a major underlying cause of either of these syndromes.[1]
Last updated: 8/8/2012

How and when might Li-Fraumeni syndrome begin in a family?

Li-Fraumeni syndrome is often caused by a mutation inherited from an affected parent (a germline mutation, which is present in the egg or sperm cells of the parent and thus in every body cell of the affected child). However, mutations that causes Li-Fraumeni syndrome can also occur only in an egg or sperm cell, or just after fertilization in an embryo. These mutations, which are "new" and have not been inherited from a parent, are referred to as de novo mutations.

A de novo mutation can occur in any egg or sperm cell, or in any embryo, and occurs spontaneously due to an error in the copying of genetic material or in an error in cell division.[3] Given that all mutations must originate at some point, someone is always going to be the first affected individual in any given affected family. Mutations that cause Li-Fraumeni syndrome are not thought to be the result of progressive instability of the disease-causing gene over generations, as is the case with many trinucleotide repeat disorders.
Last updated: 8/8/2012

Are some TP53 mutations worse than others?

Nearly 300 distinct TP53 mutations have been described in the literature. The majority of reported mutations are missense mutations, which cause the substitution of a different amino acid than was intended in the resulting protein (tumor protein p53 in this case). Deletions and splice site mutations have also been identified. It has been reported that in addition to causing the loss of the p53 protein, TP53 missense mutations may be even more likely to cause tumors than other types of mutations in the gene.[1]

Families with Li-Fraumeni syndrome do appear to display a concept known as genetic anticipation over successive generations.[1] This means that the condition may become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next.[4]

To date, there have been 2 types of genetic variations (not in the TP53 gene) that are proposed to modify the behavior of the TP53 gene and may affect the course of the condition (referred to as genetic modifiers). One of these modifiers is the MDM2 gene. Having a certain variation in the DNA of MDM2 has been associated with the development of tumors at significantly younger ages.[1] The other proposed modifier is the length of the telomeres (material at the ends of chromosomes that regulate chromosome replication during cell division) in the affected individual's chromosomes. Shortened telomere length as been associated with earlier tumor development in families with Li-Fraumeni syndrome.[1] To view a free article on PubMed that discusses this in detail, click here.

Individuals interested in further understanding and learning more about the genetic concepts related to Li-Fraumeni syndrome should speak with a genetics professional.
Last updated: 8/8/2012

How can I find a genetics professional in my area?

Genetics clinics are a source of information for individuals and families regarding genetic conditions, treatment, inheritance, and genetic risks to other family members. More information about genetic consultations is available from Genetics Home Reference. To find a genetics clinic, we recommend that you contact your primary healthcare provider for a referral.

The following online resources can help you find a genetics professional in your community:
Last updated: 10/18/2013