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Abstract

Abstract 

  1. The Li-Fraumeni syndrome (LFS) is a rare autosomal dominantly inherited disorder. It is characterized by the diagnosis of bone or soft tissue sarcoma at an early age in an individual who has one first-degree relative with early onset cancer and a second close relative with early onset cancer or sarcoma diagnosed at any age.

  2. Families in which the classic phenotype of the syndrome is not expressed completely are termed Li-Fraumeni syndrome-like (LFS-L) and are represented by many different features. Common to all these families is the occurrence of a variety of cancers of a distinct histopathologic type.

  3. Germ-line alterations of the p53 tumor-suppressor gene located on chromosome 17p13 have been observed in the majority of LFS families and in a proportion of LFS-L families. This gene encodes a 53-kDa nuclear phosphoprotein that is composed of 393 amino acids. Genetic alterations primarily result from base-pair substitutions that result in missense mutations. These changes are among the most frequently observed genetic abnormalities in human cancer. Somatic inactivation of p53 occurs through base-pair substitutions or binding to other cellular proteins or to certain DNA tumor virus proteins.

  4. The p53 protein binds specific DNA sequences and appears to be a transcription factor that may regulate the expression of other growth regulatory genes in a positive or negative manner. The antiproliferative effect of wild-type p53 is exerted at a checkpoint control site before G1/S of the cell cycle, with G2/M and the mitotic spindle being other potential targets. p53 mediates apoptosis and plays an important role in modulating the cellular response to DNA damage induced by ultraviolet (UV) irradiation or γ-irradiation and certain chemotherapeutic agents.

  5. p53 mutations are not observed in all classic LFS families. Germ-line p53 mutations are seen in a small number of patients and families with cancer phenotypes that only superficially resemble LFS. Other mechanisms of p53 inactivation may occur in some clinical settings, and other genes involved in cell cycle regulation may be altered in p53 wild-type families.

  6. Mouse models of p53 deficiency have been created. These p53 knockouts exhibit an increased rate of development of a spectrum of tumors, including lymphomas and sarcomas. Transgenic p53 mice have been generated that have a tumor phenotype distinct from that of the p53-deficient animals. Mice heterozygous for a deleted p53 allele exhibit an intermediate phenotype in that the rate of tumor formation is slower than that of the p53-null animals yet faster than that of wild-type littermates. These mice have been used as in vivo models to analyze p53 function and dysfunction in the setting of interventions with chemotherapy, radiation therapy, or teratogenic agents.

  7. Predictive genetic testing for carriers of mutant p53 is available in research settings in a few centers. The interpretation of results with respect to diagnostic capabilities and options for therapeutic intervention is under scrutiny. The value of such screening is tempered by the need to evaluate risk, counseling issues, the need for informed consent, and regulations on testing.

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