Li-Fraumeni syndrome
| Li-Fraumeni syndrome | |
|---|---|
| Classification and external resources | |
| ICD-9 | 758.3 |
| OMIM | 151623 |
| DiseasesDB | 7450 |
| eMedicine | ped/1305 |
| MeSH | D016864 |
Li-Fraumeni syndrome is an extremely rare autosomal dominant hereditary disorder. Named after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first recognized and described the syndrome,[1] Li-Fraumeni syndrome greatly increases susceptibility to cancer.
The syndrome is linked to germline mutations of the p53 tumor suppressor gene,[2] which normally helps control cell growth. Mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.
Because the TP53 gene is responsible for initiating DNA repair mechanisms and/or apoptosis upon detection of DNA damage, Li-Fraumeni syndrome, with one of the two p53 copies already mutated, predisposes a person to cancer development because only one additional mutation (in the second p53 allele) is necessary to impair a significant portion of the tumor suppressor system. This "second hit", which can be effected by environmental factors, can directly lead to both p53 alleles being impaired and thus potentiate cancer development. Indeed, persons with LFS have an approximately 25-fold risk of developing a malignant tumor by age 50 than the population average, and 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.[3]
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[edit] Characteristics
Unusually, Li-Fraumeni syndrome is characterised by:
- several kinds of cancer are involved;
- cancer often appears at a young age; and,
- cancer often appears several times throughout the life of an affected person.
[edit] 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.
[edit] Pathology
- LFS1: The TP53 (tumor suppressor gene p53) normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 assists in repair or destruction of "bad" DNA before it can enter the normal cell cycle, thus preventing abnormal and/or cancerous growth of cells. Mutations of TP53 prevent this normal function and allow damaged cells to divide and grow in an uncontrolled, unchecked manner forming tumors (cancers). TP53 mutations have been primarily implicated in Li-Fraumeni.
- LFS2: A variant of Li-Fraumeni does not have a mutation in TP53 but instead has mutation of the CHEK2 (or CHK2) gene. CHK2 is also a tumor suppressor gene. The complete implication of this mutation is not known, but CHK2 regulates the action of p53. CHK2 is activated by ATM which detects DNA damage, and in this way DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death).
[edit] See also
[edit] References
- ^ Li F.P., Fraumeni J.F. (October 1969). "Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?". Ann. Intern. Med. 71 (4): 747–52. PMID 5360287.
- ^ Varley J.M. (March 2003). "Germline TP53 mutations and Li-Fraumeni syndrome". Hum. Mutat. 21 (3): 313–20. doi:10.1002/humu.10185. PMID 12619118.
- ^ Ramzi Cotran, Vinay Kumar, Tucker Collins (2010). Robbins Pathologic Basis of Disease, 8th Edition. W.B. Saunders. pp. 288-290. ISBN 1437707920.
[edit] External links
- Li-Fraumeni syndrome, in the National Library of Medicine Genetics Home Reference (an introduction to the disease)
- Li-Fraumeni Syndrome by Katherine A Schneider and Frederick Li, in GeneReviews, a section of GeneTests, published online by the University of Washington with funds from the National Institutes of Health
- Li-Fraumeni syndrome; LFS1, entry in Online Mendelian Inheritance in Man (OMIM), published by Johns Hopkins University and the National Institutes of Health
- The George Pantziarka TP53 Trust A support group from the UK for sufferers of Li-Fraumeni Syndrome or other TP53-related disorders
- European Li-Fraumeni Families Foundation ELFF
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