Li+Fraumeni+Syndrome

=Li Fraumeni Syndrome=

This syndrome is characterized by a mutations in the TP53 or CHEK2 tumor suppressor genes, and as a result, individuals with this syndrome have much higher rates of cancer, specifically; sarcoma, breast, leukaemia, and adrenal gland cancers [1][2]. When damage to DNA is detected by the cell, a signal is sent to the CHEK2 gene which activates the TP53 gene; the TP53 gene transcribes a protein that initiates DNA repair and/or apoptosis. Mutations to this gene result in a missing regulatory pathway that allows cells with irregular DNA to progress through cell cycles normally and divide; this predisposes individuals with this syndrome to roughly 25 fold increased risk of developing a malignant tumor by the age of fifty[1]. Li Fraumeni syndrome is inherited through an autosomal dominant pathway, which means that an abnormal TP53 gene must be inherited from only one parent in order for the offspring to develop with this syndrome. The autosomal dominant pathway in this syndrome is characterized by a dominant negative mutation of the genes, which produce abnormal proteins that inactivate normal tumor suppressor proteins, so a heterogeneous individual will always have this syndrome. There are three characteristic variants of Li Fraumeni Syndrome; LFS1, LFS2, and a third locus on chromosome 1 related to an unidentified gene [2]. In the type I variant of Li Fraumeni, a mutation occurs on the TP53 gene directly [1][3]. This is usually associated with a premature stop codon which truncates the protein. There are eleven exons in this gene, and in most cases the mutations occur on exons five through eight, generally the remaining cases have mutations in either exon four or nine. The type II variant of Li Fraumeni contains one or more mutations on the CHEK2 gene, which regulates the TP53 gene[1][3]. Normally the CHEK2 gene receives a signal from ATM protein that detects DNA damage, and then activates the TP53 gene. A mutated CHEK2 gene is not able to convey the message that there is DNA damage to TP53 and the cell progresses through normal cell cycle with repair to DNA. Li Fraumeni type III is not characterized by a known gene, but the locus has been mapped to chromosome one [1]. Many cancers, particularly breast cancer, are at a much higher risk in individuals with Li Fraumeni that the normal population with ~100% lifetime risk in females and 73% in males to develop cancer.

Fact Sheet:


 * Name of Disease**: Li-Fraumeni Syndrome
 * Root cause of Disease**: Irregularities in the normal function of the TP53 gene, which is responsible for initiating DNA repair mechanisms and/or apoptosis when DNA damage is detected.
 * Affected Cell Types**: Cell types involved in rapid division as well as nerve tissues are at a higher risk. The result is an amplified risk of all types of cancer, with higher rates among already high risk areas (breast, blood, sarcoma, adrenal gland, and brain cancers).
 * Historical Background**: The syndrome was first characterized by Frederick Pei Li and Joseph F. Fraumeni Jr., of whom the disease is named after.
 * Common Symptoms**: Several types of cancer, cancer development at a young age, cancer that appears several times throughout the lifetime of the affected individual.
 * Standard Treatments**: Genetic counseling and genetic testing are used to confirm the syndrome. Once a positive diagnosis is determined, regular cancer screenings are preformed. Radiation therapy is not done in an effort to reduce secondary radiation induced malignancies. Prophylactic mastectomy is an option to reduce the risk of breast cancer.
 * Current Research**: Current research is focused on early detection of cancer in LFS patients, and non-radiation treatment of these cancers. Physicians at Dana-Farber have been able to detect three types of cancer in asymptomatic LFS patients using PET-CT and full body MRI scanning techniques. There is also evidence that the types of breast cancer that arise in LFS are generally the types that can be treated by a targeted drug (monoclonal antibody that decreases the expression of HER2 gene), Trastuzumab (Herceptin) [4].

References

[1] Varley, J. (2003). Germline TP53 Mutations and Li-Fraumeni Syndrome. Hum. Mutat. 21 (3). 313-320

[2] Cotran, R. Kumar, V. Collins, T. (2010). Robbins Pathologic Basis of Disease. (8) pp 288-290

[3] Birch, JM. Harley, AL. Tricker, K. Prosser, J. Condie, A. Kelsey, A. Harries, M. Jones, P. Binchy, A. Crowther, D. Craft, A. Eden, O. Evans, D. Thompson, E. Mann, J. Martin, J. Mitchell, E. Santibanez-Koref, M. (1994). Prevalence and Diversity of Constitutional Mutations in the P53 Gene Among 21 Li-Fraumeni Families. Cancer Res. 54. pp 1298-304

[4] Hudis, CA. (2007). Trastzumab—Mechanism of Action and Use in Clinical Practice. N Engl. J Med. 357 (1). 39-51