Disease relevance of Li-Fraumeni Syndrome

• We have now analysed the p53 gene in a family affected by Li-Fraumeni syndrome, a rare autosomal dominant syndrome characterized by the occurrence of diverse mesenchymal and epithelial neoplasms at multiple sites [1].
• BACKGROUND: Heritable germline mutations of the p53 gene have been described in patients with Li-Fraumeni syndrome, occasionally in nonfamilial malignancies such as multifocal osteosarcoma, in a small subgroup of young patients with two or more primary malignancies, and in patients with sporadic breast carcinoma [2].
• Sarcomas occur at high frequency in individuals with Li-Fraumeni syndrome as well as in p53-deficient mice [3].
• Ataxia-telangiectasia and Li-Fraumeni syndrome, pleiotropic disorders caused by mutations in the genes atm and p53, share a marked increase in cancer rates [4].
• Therefore, the BALB/c-p53(+/-) mice provide a unique model for the study of breast cancer in Li-Fraumeni syndrome [5].

High impact information on Li-Fraumeni Syndrome

• Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome [6].
• Individuals with Li-Fraumeni syndrome carry inherited mutations in the p53 tumor suppressor gene and are predisposed to tumor development [7].
• To ascertain the physiological effects of p53 point mutation, the structural mutant p53R172H and the contact mutant p53R270H (codons 175 and 273 in humans) were engineered into the endogenous p53 locus in mice. p53R270H/+ and p53R172H/+ mice are models of Li-Fraumeni Syndrome; they developed allele-specific tumor spectra distinct from p53+/- mice [6].
• CONCLUSIONS: Our observation of a high frequency of germline TP53 mutations in children with sporadic ADCC suggests that these children may represent probands with which to ascertain Li-Fraumeni syndrome families [8].
• Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome [9].

Chemical compound and disease context of Li-Fraumeni Syndrome

• We have shown previously that Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in the removal of UV-induced cyclobutane pyrimidine dimers from genomic DNA, but still proficient in the transcription-coupled repair pathway (Ford, J. M., and Hanawalt, P. C. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 8876-8880) [10].
• Acute myelogenous leukemia in a patient with Li-Fraumeni syndrome treated with valproic acid, theophyllamine and all-trans retinoic acid: a case report [11].
• The importance of oligomerization is underscored by the observation that substitution of isoleucine for threonine at position 157, a mutation found in a subset of patients with Li-Fraumeni syndrome, impairs both Chk2 oligomerization and autophosphorylation [12].

Biological context of Li-Fraumeni Syndrome

• It appears that the group of patients with cancer who carry germline mutations of the p53 gene is more diverse than is suggested by the clinical definition of the Li-Fraumeni syndrome [13].
• Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts [14].
• Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome [15].
• This is the first report where germline transmission of replication-damaged p53 trinucleotide repeats is associated with the Li-Fraumeni syndrome [16].
• RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome [17].

Anatomical context of Li-Fraumeni Syndrome

• Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome [1].
• A novel, de novo germline TP53 mutation in a rare presentation of the Li-Fraumeni syndrome in the maxilla [18].

Gene context of Li-Fraumeni Syndrome

• BALB/c-Trp53(+/-) mice are a model of Li-Fraumeni syndrome, exhibiting a high frequency of mammary tumors and other tumor types seen in patients [19].
• In GM38A cells, the substantially induced levels of MKP-1 correlated with the transient activation of ERK1/2 by PDT, and both basal and induced levels of MKP-1 were substantially greater in GM38 compared with Li Fraumeni syndrome cells [20].
• Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene [21].
• Both germline and somatic loss-of-function CHEK2 mutations occur in human tumours, the former linked to the Li-Fraumeni syndrome, and the latter found in diverse types of sporadic malignancies [22].
• Telomerase activity during spontaneous immortalization of Li-Fraumeni syndrome skin fibroblasts [23].

Analytical, diagnostic and therapeutic context of Li-Fraumeni Syndrome

• Inactivation of the p53 gene in the germline of mice by gene targeting has provided researchers with a model similar in many respects to the analogous human inherited cancer predisposition Li-Fraumeni syndrome [24].

References