Li–Fraumeni Syndrome

Abstract

The Li–Fraumeni syndrome is a rare inherited predisposition to the development of multiple cancer phenotypes at an early age which is attributed primarily to germline mutations of the p53 tumour suppressor gene. Identification of these families is important in the study of cancer and the development of ethical and appropriate screening modalities, prevention, early cancer detection, and treatment of individuals who harbour alterations of such cancer genes, in order that we may one day improve their prognosis.

Keywords: tumour suppressor gene; p53; li–fraumeni syndrome; cell cycle; predictive screening

Figure 1.

Classical Li–Fraumeni pedigree. Squares represent males and circles represent females. Shaded symbols represent affected individuals. Crossed individuals are deceased. Numbers indicate age at diagnosis.

Figure 2.

p‐53 consists of 393 amino acids with four structural and five evolutionarily conserved domains (purple boxes). The four structural domains are the transactivation domain (codons 1–42; red), the central DNA‐binding domain (codons 102–292; orange), the tetramerization domain (codons 324–355; blue) and the regulatory domain (codons 367–393; green). Note the mutational hotspots (pink bars) within the conserved domains. Examples of protein and viral binding sites are indicated, which can also lead to inhibition of p‐53 function.

Figure 3.

p‐53 at the G1–S phase of the cell cycle. DNA damage leads to p‐53 accumulation, resulting in cell cycle arrest to allow for DNA repair. If the damage is too great for repair, then p‐53 can lead to apoptosis to prevent propagation of genetic changes. E2F represents a family of transcription factors. Cdk, cyclin‐dependent kinase; P, phosphate group; pRb, Retinoblastoma protein.

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References

Donehower LA, Harvey M, Slagle BL et al. (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.

Eeles RA (1995) Germline mutations in the TP53 gene. Cancer Surveys 25: 101–124.

Hollstein M, Rice K, Greenblatt MS et al. (1994) Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Research 22: 3551–3555.

Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the USA 68: 820–823.

Kuerbitz SJ, Plunkett BS, Walsh WV and Kastan MB (1992) Wild‐type p53 is a cell cycle checkpoint determinant following irradiation. Proceedings of the National Academy of Sciences of the USA 89: 7491–7495.

Li FP, Fraumeni JF Jr, Mulvihill JJ et al. (1988) A cancer family syndrome in twenty‐four kindreds. Cancer Research 48: 5358–5362.

Malkin D, Li FP, Strong LC et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233–1238.

Varley JM, McGown G, Thorncroft M et al. (1999) Are there low‐penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. American Journal of Human Genetics 65: 995–1006.

Venkatachalam S, Shi YP, Jones SN et al. (1998) Retention of wild‐type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO Journal 17: 4657–4667.

Williams W and Strong L (1985) Genetic epidemiology of soft tissue sarcomas in children. In: Muller H and Weber W (eds) Familial Cancer. First International Research Conference, pp. 151–153. Basel, Switzerland: Karger

Further Reading

Bischoff FZ, Yim SO, Pathak S et al. (1990) Spontaneous abnormalities in normal fibroblasts from patients with Li–Fraumeni cancer syndrome: aneuploidy and immortalization. Cancer Research 50: 7979–7984.

Cho Y, Gorina S, Jeffrey PD and Pavletich NP (1994) Crystal structure of a p53 tumor suppressor–DNA complex: understanding tumorigenic mutations. Science 265: 346–355.

Harvey M, McArthur MJ, Montgomery CA Jr, Bradley A and Donehower LA (1993) Genetic background alters the spectrum of tumors that develop in p53‐deficient mice. FASEB Journal 7: 938–943.

Lamb P and Crawford L (1986) Characterization of the human p53 gene. Molecular and Cellular Biology 6: 1379–1385.

Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358: 15–16.

Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

Li FP and Fraumeni JF Jr (1969) Soft‐tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Annals of Internal Medicine 71: 747–752.

Tainsky MA, Bischoff FZ and Strong LC (1995) Genomic instability due to germline p53 mutations drives preneoplastic progression toward cancer in human cells. Cancer Metastasis Reviews 14: 43–48.

Varley JM, Evans DG and Birch JM (1997) Li–Fraumeni syndrome – a molecular and clinical review. British Journal of Cancer 76: 1–14.

Varley JM, McGown G, Thorncroft M et al. (1997) Germ‐line mutations of TP53 in Li–Fraumeni families: an extended study of 39 families. Cancer Research 57: 3245–3252.

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How to Cite close
Portwine, Carol, and Malkin, David(Apr 2001) Li–Fraumeni Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0001893]