Li-Fraumeni syndrome

Shay, J. W., G. Tomlinson, M. A. Piatyszek, and L. S. Gollahon. 1995. Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol Cell Biol 15(l) 425-32. 

Rogan, E. M., T. M. Bryan, B. Hukku, K. Maclean, A. C. Chang, E. L. Moy, A. Englezou, S. G. Wameford, L. Dalla-Pozza, and R. R. Reddel. 1995. Alterations in p53 and pl6INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. Mol Cell Biol 15(9) 4745-53. 

The p53 gene encodes a protein that prevents a cell with damaged DNA from entering the S phase. Inactivation or deletion associated with Li Fraumeni syndrome and many solid tumors. 

Dominant effect at the cellular level of a recessively inherited loss-of-function mutant of a tumor suppressor gene (see Chapter 14) Retinoblastoma and RBI Li-Fraumeni syndrome and TP53... 

Patients with Li-Fraumeni syndrome have increased susceptibility to a variety of cancers, including bone and soft-tissue sarcomas, breast tumors, brain cancers, leukemia, and adrenocortical carcinoma, all arising at an early age (often before 30 years). 

The incidence of Li-Fraumeni syndrome has not been calculated because it is so rare. 

Mutations of the p53 gene are observed in over 50 % of all human tumors. Defects in the p53 gene in the germ line lead to a hereditary tendency to develop various tumors, especially of the connective tissue. In affected families, several members of the family may develop tumors during childhood. The disease is known as Li Fraumeni Syndrome after its discoverer. 

TP53 Li-Fraumeni syndrome Transcription factor Most human cancers... 

Tumour-suppressor gene The tumour-suppressor gene p53 is located on chromosome 17. Noxae may cause mutations of this gene, which results in the loss of its suppressor effect. (6, 126) An autosomal dominant mutation of p53 is also encountered in humans, so that a tumour can develop during adolescence, the so-called Li-Fraumeni syndrome. 

Mutations in p53 occur in spontaneous and inherited cancers. The role of p53 in DNA repair appears to be to momentarily halt the progression of the cell cycle, so as to give various DNA repair enzymes a chance to complete their job, prior to initiation of DNA synthesis. Overall, p53 is mutated in about half of all human cancers. Li-Fraumeni syndrome is a rare type of cancer that involves an inherited mutation in p53. About 50% of the affected persons acquire cancer by the age of 30 (Harvey et ah, 1995). 

BRCA2 Li-Fraumeni syndrome Soft tissue sarcomas in... 

Srivastava, S., Zou, Z., Pirollo, K., Blattner, W., and Chang, E. (1990) Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348,747-749. 

Most mutations of p53 genes are somatic missense mutations involving amino acid substitutions in the DNA binding domain. The mutant forms of p53 are misfolded proteins with abnormal conformations and the inability to bind to DNA, or they are less stable. Individuals with the rare disorder Li-Fraumeni syndrome, (an autosomal dominant trait) have one mutated p5 > gene and one normal p53 gene. These individuals have increased susceptibility to many cancers, such as leukemia, breast carcinomas, soft-tissue sarcomas, brain tumors, and osteosarcomas. 

D. Malkin p53 and the Li-Fraumeni syndrome. Biochimica Biophysica Acta 1198,197(1994). 

Ford JM, Hanawalt PC (1995) Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci USA 92 8876-80 Hwang BJ, Ford JM, Hanawalt PC, Chu G (1999) Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci USA 96 424-8... 

Approximately half of the families with the Li-Fraumeni cancer syndrome carry one mutant p53 allele in somatic cells (Malkin et al., 1990 Srivastava et al., 1990 see review in Kleihues et al., 1997). This disease is characterized by familial clustering of various cancers, particularly early-onset breast cancer, sarcomas, leukemias, and brain and adrenocortical tumors. Mice with targeted nonfunctional p53 alleles provide an experimental model for this disorder. Early spontaneous tumors, primarily lymphomas and sarcomas, arise frequently in p53 / and p53+/ mice, reflecting the Li-Fraumeni syndrome in these respects. Curiously, mammary and brain tumors are uncommon in p53 knockout mice (Donehower, 1996b Eng et al., 1997). 

Inheritance of a mutation in p53 leads to Li-Fraumeni syndrome, which is characterized by multiple types of tumors. Mutations in p53 are present in more than 50% of human tumors. These are secondary mutations within the cell, and if p53 is mutated the overall rate of cellular mutation will increase because there is no p53 to check for DNA damage, to initiate the repair of the damaged DNA, or to initiate apoptosis if the damage is not repaired. Thus, damaged DNA is replicated, and the frequency of additional mutations within the same cell increases remarkably. 

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