Li-Fraumeni syndrome

Li-Fraumeni syndrome is a rare autosomal dominant hereditary disorder. It is named after Frederick Pei Li and Joseph F. Fraumeni, American physicians who originally described the syndrome. It increases greatly the susceptibility to cancer. The syndrome is a mutation in the p53 tumor suppressor gene, which normally helps control cell growth.

Tumor types

The tumors that occur at an increased rate are:

Characteristics

What makes Li-Fraumeni Syndrome unusual is that

several kinds of cancer are involved,
cancer often strikes at a young age, and
cancer often strikes several times throughout the life of somebody with the syndrome.

Diagnosis and treatment

Li-Fraumeni Syndrome is diagnosed if the following three criteria are met:

the patient has been diagnosed with a sarcoma at a young age (below 45),
a first-degree relative has been diagnosed with any cancer at a young age (below 45),
and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.

Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her. If caught early the cancers can often be successfully treated. Unfortunately, people with Li-Fraumeni are likely to develop another primary malignancy at a future time.

Pathophysiology

At the molecular level Li-Fraumeni Syndrome is caused by mutations in p53, a tumor suppressor gene. Normally loss of function mutations in a tumor suppressor gene behaves in recessive manner, meaning that an individual needs to inherit two mutant copies of the tumor suppressor gene in order to be inflicted. However, as indicated by many pedigree analyses of families with this disease, Li-Fraumeni Syndrome is inherited in an autosomal dominant manner, with diseased individuals at each generation with no non-diseased carriers in between.

p53, as a transcription factor, tetramerizes before binding to DNA to transactivate genes involved in inducing DNA repair, cell cycle arrest, and senescence. In most cases, individuals with Li-Fraumeni Syndrome have p53 mutations within the DNA-binding domain. And a defective p53, when tetramerized with other wildtype p53s, actually "poisons" the wildtype, rendering the whole tetramer nonfunctional (this is known as dominant negative effect). Therefore mutation in one copy of p53 is enough to generate uncontrolled cell division. As a result, inheriting one defective copy of p53 predisposes an individual to lower cancer latency.

Reference

Li FP, Fraumeni Jr JF. Soft-tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann Intern Med 1969;71:747-52. PMID 5360287.

External links

http://www.geneclinics.org/profiles/li-fraumeni/details.html
http://www.emedicine.com/ped/topic1305.htm

Oncology | Eponymous diseases | Hereditary cancers | Genetic disorders