Li–Fraumeni Syndrome

  • David MalkinEmail author


In 1969, a remarkable cancer predisposition syndrome was reported by Li and Fraumeni. Using a classical epidemiologic approach, they retrospectively evaluated 280 medical charts and 418 death certificates of children diagnosed with rhabdomyosarcoma in the United States from 1960 to 1964 [1,2]. Five families were identified in whom a second child had developed a soft tissue sarcoma. In addition, a high frequency of diverse cancer types were observed among the first- and second degree adult relatives along one ancestral line of each proband with cancer rates considerably in excess of those expected by chance alone. In addition to soft tissue sarcomas and pre-menopausal breast cancers, carcinomas of the lung, skin, pancreas or adrenal cortex, leukemia, and various brain tumors were also observed. Multiple metachronous primary neoplasms were also observed in several family members. Li and Fraumeni suggested that the occurrence of diverse neoplasms in these families might represent a counterpart of the tendency for a single individual to develop multiple primary tumors, and that these families represented a previously undescribed familial cancer syndrome, with transmission suggestive of an autosomal dominant gene.


TP53 Mutation Copy Number Variable Region MDM2 SNP309 Choroid Plexus Carcinoma TP53 Protein 
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  1. 1.
    Li FP, Fraumeni Jr JF (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4):747–752Google Scholar
  2. 2.
    Li FP, Fraumeni JF Jr (1969) Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43:1365–1373PubMedGoogle Scholar
  3. 3.
    Li FP et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362Google Scholar
  4. 4.
    Nichols KE et al (2001) Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemol Biomark Preven 10(2):83–87Google Scholar
  5. 5.
    Birch JM et al (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54:1298–1304PubMedGoogle Scholar
  6. 6.
    Chompret A et al (2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43–47CrossRefPubMedGoogle Scholar
  7. 7.
    Tinat J et al (2009) version of the Chompret criteria for Li-Fraumeni syndrome. J Clin Oncol 27(26):e108–109Google Scholar
  8. 8.
    Hisada M et al (1998) Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 90:606–611CrossRefPubMedGoogle Scholar
  9. 9.
    Wu CC et al (2006) Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res 66:8287–8292CrossRefPubMedGoogle Scholar
  10. 10.
    Hwang SJ et al (2003) Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 72:975–983CrossRefPubMedGoogle Scholar
  11. 11.
    DeLeo AB et al (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci USA 76:2420–2424CrossRefPubMedGoogle Scholar
  12. 12.
    Lane DP, Crawford LV (1979) T antigen bound to a host protein in SV40-transformed cells. Nature 278:261–263CrossRefPubMedGoogle Scholar
  13. 13.
    Linzer DI, Levine AJ (1979) Characterization of a 54 K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 417:43–52CrossRefGoogle Scholar
  14. 14.
    McBride OW et al (1986) The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci USA 83:130–134CrossRefPubMedGoogle Scholar
  15. 15.
    Soussi T (2007) Oncogene. p53 alterations in human cancer: more questions than answers. 26:2145–2156Google Scholar
  16. 16.
    Soussi T et al (1990) Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5:945–952PubMedGoogle Scholar
  17. 17.
    Addison C et al (1990) The p53 nuclear localization signal is structurally linked to a p34cdc2 kinase motif. Oncogene 5:423–426PubMedGoogle Scholar
  18. 18.
    Farmer G et al (1992) Wild-type p53 activates transcription in vitro. Nature 358:83–86CrossRefPubMedGoogle Scholar
  19. 19.
    Jenkins JR et al (1988) Two distinct regions of the murine p53 primary amino acid sequence are implicated in stable complex formation with simian virus 40 T antigen. J Virol 62:3903–3906PubMedGoogle Scholar
  20. 20.
    Meek DW, Eckhart W (1988) Phosphorylation of p53 in normal and simian virus 40-transformed NIH3T3 cells. Mol Cell Biol 8:461–465PubMedGoogle Scholar
  21. 21.
    Milner J. Medcalf EA (1991) Cotranslation of activated mutant p53 with wild-type drives the wild-type p53 protein into the mutant conformation. Cell 65:765–774CrossRefPubMedGoogle Scholar
  22. 22.
    Kubbutat MH, Vousden KH (1997) Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability. Mol Cell Biol 17:460–468PubMedGoogle Scholar
  23. 23.
    Kubbutat MH et al (1997) Regulation of p53 stability by Mdm2. Nature 387:299–303CrossRefPubMedGoogle Scholar
  24. 24.
    Jayaraman L, Prives C (1999) Covalent and noncovalent modifiers of the p53 protein. Cell Mol Life Sci 55:76–87CrossRefPubMedGoogle Scholar
  25. 25.
    Sionov RV et al (2001) c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Mol Cell Biol 21:5869–5878CrossRefPubMedGoogle Scholar
  26. 26.
    Hermeking LC et al (1997) 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1:3–11CrossRefPubMedGoogle Scholar
  27. 27.
    Zhan Q et al (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18:2892–2900CrossRefPubMedGoogle Scholar
  28. 28.
    Lane DP (1992) p53, guardian of the genome. Nature 358:15–16CrossRefPubMedGoogle Scholar
  29. 29.
    Rosse T et al (1998) Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391:496–499CrossRefPubMedGoogle Scholar
  30. 30.
    Muller M et al (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188:2033–2045CrossRefPubMedGoogle Scholar
  31. 31.
    Wu GS et al (1997) KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genet 17:141–143CrossRefPubMedGoogle Scholar
  32. 32.
    Vogelstein B. Kinzler KW. (1994) Tumor-suppressor genes. X-rays strike p53 again. Nature 370:174–175CrossRefPubMedGoogle Scholar
  33. 33.
    Kern SE et al (1992) Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256:827–830CrossRefPubMedGoogle Scholar
  34. 34.
    Kern SE et al (1991) Identification of p53 as a sequence-specific DNA-binding protein. Science 252:827–830CrossRefGoogle Scholar
  35. 35.
    Ruijs MWG et al (2006) The single nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Human Genet [adv online pub]Google Scholar
  36. 36.
    Oliner JD et al (1992) Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358:80–83CrossRefPubMedGoogle Scholar
  37. 37.
    Malkin D et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238Google Scholar
  38. 38.
    Baker SJ et al (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221CrossRefPubMedGoogle Scholar
  39. 39.
    Lavigueur A et al (1989) High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9:3982–3991PubMedGoogle Scholar
  40. 40.
    Kleihues P et al (1997) Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150:1–13PubMedGoogle Scholar
  41. 41.
    Tsukada T et al (1993) Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene 8:3313–3322PubMedGoogle Scholar
  42. 42.
    Olivier M et al (2003) Li-Fraumeni and related syndromes: correlation between tumor type family structure, and TP53 genotype. Cancer Res 63:6643–6650PubMedGoogle Scholar
  43. 43.
    Varley JM, Germline (2003) TP53 mutations and Li-Fraumeni syndrome. Human Mutation 21:313–320CrossRefPubMedGoogle Scholar
  44. 44.
    Lalloo F et al (2003) Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet 361:1101–1102CrossRefPubMedGoogle Scholar
  45. 45.
    Quesnel S et al (1999) p53 compound heterozygosity in a severely affected child with Li-Fraumeni syndrome. Oncogene 18:3970–3978CrossRefPubMedGoogle Scholar
  46. 46.
    Gannon JV et al (1990) Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J 9:1595–1602PubMedGoogle Scholar
  47. 47.
    Srivastava S et al (1993) Several mutant p53 proteins detected in cancer-prone families with Li-Fraumeni syndrome exhibit transdominant effects on the biochemical properties of the wild-type p53. Oncogene 8:2449–2456PubMedGoogle Scholar
  48. 48.
    Bougeard G et al (2001) Detection of 11 germline inactivating TP53 mutations and abse nce of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. J Med Genet 38(4):253–257CrossRefPubMedGoogle Scholar
  49. 49.
    Stone JG et al (1999) Analysis of Li-Fraumeni syndrome and Li-Fraumeni-like families for germline mutations in Bcl10. Cancer Lett 147:185–189CrossRefGoogle Scholar
  50. 50.
    Barlow JW et al (2004) Germline BAX alterations are infrequent in Li-Fraumeni Syndrome. Cancer Epid Biomark Prev 13:1403–1406Google Scholar
  51. 51.
    Burt EC et al (1999) Exclusion of the genes CDKN2 and PTEN as causative gene defects in Li-Fraumeni syndrome. Br J Cancer 80:9CrossRefPubMedGoogle Scholar
  52. 52.
    Portwine C et al (2000) Absence of p16INK4a alterations in p53 wild-type Li-Fraumeni syndrome families. J Med Genet 37:e13Google Scholar
  53. 53.
    Brown LTR et al (2000) Identification of a novel PTEN intronic deletion in Li-Fraumeni syndrome and its effect on RNA processing. Cancer Genet Cytogenet 123:65CrossRefPubMedGoogle Scholar
  54. 54.
    Bell DW et al (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528–2531CrossRefPubMedGoogle Scholar
  55. 55.
    Vahteristo P et al (2001) p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res 61(15):5718–5722PubMedGoogle Scholar
  56. 56.
    Sodha N et al (2000) Screening hCHK2 for mutations. Science 289:359CrossRefPubMedGoogle Scholar
  57. 57.
    Cybulski C et al (2008) Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers. Carcinogenesis 29:762–765CrossRefPubMedGoogle Scholar
  58. 58.
    Meijers-Heijboer H et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genet 31:55–59CrossRefPubMedGoogle Scholar
  59. 59.
    Bachinski LL et al (2005) Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res 65:427–431PubMedGoogle Scholar
  60. 60.
    Bond GL et al (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66:5104CrossRefPubMedGoogle Scholar
  61. 61.
    Bougeard G et al (2006) Impact of the MDM SNP309 and p53 Arg72Pro polymorphism on age of onset in Li-Fraumeni syndrome. J Med Genet 43:531–533CrossRefPubMedGoogle Scholar
  62. 62.
    Trkova M et al (2002) Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome? J Hum Genet 47(8):381–386CrossRefPubMedGoogle Scholar
  63. 63.
    Tabori U et al (2007) Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res 67(4):1415–1418CrossRefPubMedGoogle Scholar
  64. 64.
    Trkova M et al (2007) Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 110(3):694–702CrossRefPubMedGoogle Scholar
  65. 65.
    Marcel V et al (2009) TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. J Med Genet 46:766–772CrossRefPubMedGoogle Scholar
  66. 66.
    Shlien A et al (2008) Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci USA 105(32):11264–11269CrossRefPubMedGoogle Scholar
  67. 67.
    Shlien A, Malkin D (2009) Copy number variations and cancer. Genome Med 1(6):62–67CrossRefPubMedGoogle Scholar
  68. 68.
    Figueiredo BC et al (2006) Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 43(1):91–96CrossRefPubMedGoogle Scholar
  69. 69.
    Ribeiro RC et al (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330–9335CrossRefPubMedGoogle Scholar
  70. 70.
    Achatz MI et al (2007) The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 245(1–2):96–102CrossRefPubMedGoogle Scholar
  71. 71.
    DiGiammarino EL et al (2002) A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9(1):12–16CrossRefPubMedGoogle Scholar
  72. 72.
    Palmero EI et al (2007) Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. Cancer Lett 261: 21–25CrossRefGoogle Scholar
  73. 73.
    Garritano S et al (2010) Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Human Mut 31(2):143–150Google Scholar
  74. 74.
    Frebourg T et al (1992) Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. Proc Natl Acad Sci 89:6413–6417CrossRefPubMedGoogle Scholar
  75. 75.
    Frebourg T et al (1992) A functional screen for germ line p53 mutations based on transcriptional activation. Cancer Res 52:6967–6968Google Scholar
  76. 76.
    Flaman JM et al (1995) A simple p53 functional assay for screening cell lines, blood, and tumors. Proc Natl Acad Sci 92:3963–3967CrossRefPubMedGoogle Scholar
  77. 77.
    Ishioka C et al (1993) Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nature Genet 5:124–129CrossRefPubMedGoogle Scholar
  78. 78.
    Weisz L et al (2004) Transactivation of the EGR1 gene contributes to mutant p53 gain of function. Cancer Res 64:8318–8327CrossRefPubMedGoogle Scholar
  79. 79.
    Willis A et al (2004) Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene 23:2330–2338CrossRefPubMedGoogle Scholar
  80. 80.
    Boyle JM et al (1998) Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families. Br J Cancer 77:2181–2192PubMedCrossRefGoogle Scholar
  81. 81.
    Camplejohn RS et al (1995) A possible screening test for inherited p53-related defects based on the apoptotic response of peripheral blood lymphocytes to DNA damage. Br J Cancer 72:654–662PubMedCrossRefGoogle Scholar
  82. 82.
    Goi K et al (1998) DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation. Cancer Res 57:1895–1902Google Scholar
  83. 83.
    Yoon DS et al (2002) Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am J Pathol 161:391–397PubMedGoogle Scholar
  84. 84.
    Donehower LA et al (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221CrossRefPubMedGoogle Scholar
  85. 85.
    Jacks T et al (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4:1–7CrossRefPubMedGoogle Scholar
  86. 86.
    Purdie CA et al (1994) Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9:603–609PubMedGoogle Scholar
  87. 87.
    Donehower LA (1996) The p53-deficient mouse: a model for basic and applied cancer studies. Semin Cancer Biol 7:269–278CrossRefPubMedGoogle Scholar
  88. 88.
    Harvey M et al (1993) Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet 5:225–229CrossRefPubMedGoogle Scholar
  89. 89.
    Kuperwasser C et al (2000) Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. Am J Pathol 157:2151–2159Google Scholar
  90. 90.
    Varley JM et al (2001) Characterization of germline TP53 splicing mutations and their genetic and functional analysis. Oncogene 20:2647–2654CrossRefPubMedGoogle Scholar
  91. 91.
    Chene P (1998) In vitro analysis of the dominant negative effect of p53 mutants. J Mol Biol 281:205–209Google Scholar
  92. 92.
    Venkatachalam S et al (1998) Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. Embo J 17:4657–4667CrossRefPubMedGoogle Scholar
  93. 93.
    Rangarajan A, Weinberg RA (2003) Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959Google Scholar
  94. 94.
    Liu G et al (2000) High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci USA 97:474–4179Google Scholar
  95. 95.
    Lang GA et al (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861–872CrossRefPubMedGoogle Scholar
  96. 96.
    Olive KP et al (2004) Mutant p53 gain-of-function in two mouse models of Li-Fraumeni syndrome. Cell, 119:847–860CrossRefPubMedGoogle Scholar
  97. 97.
    Liu G et al (2004) Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36:63–68CrossRefPubMedGoogle Scholar
  98. 98.
    Masciari S et al (2008) F18-fluorodeoxyglucose positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. J Amer Med Assoc 299(11):1315–1319CrossRefGoogle Scholar
  99. 99.
    Hwang SM et al (2008) Genetic counseling can influence the course of a suspected familial cancer syndrome patient: from a case of Li-Fraumeni like syndrome with a germline mutation in the TP53 gene. Korean J Lab Med 28(6):493–497CrossRefPubMedGoogle Scholar
  100. 100.
    Lin MT et al (2009) Early detection of adrenocortical carcinoma in a child with Li-Fraumeni syndrome. Pediatr Blood Cancer 52(4):541–544CrossRefPubMedGoogle Scholar
  101. 101.
    Evans DG et al (2010) Childhood predictive genetic testing for Li-Fraumeni syndrome. Fam Cancer 9(1):65–69Google Scholar
  102. 102.
    Lammens C et al (2009) Attitudes towards pre-implantation genetic diagnosis for hereditary cancer. Fam Cancer 8(4):457–464Google Scholar
  103. 103.
    Peterson SK et al (2008) Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome. Psychooncology 17(8):782–789Google Scholar
  104. 104.
    Schwarzbraun T et al (2009) Predictive diagnosis of the cancer-prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing. J Med Genet 46(5):341–344CrossRefPubMedGoogle Scholar
  105. 105.
    Croyle RT et al (1997) Psychologic aspects of cancer genetic testing—A research update for clinicians. Cancer 80:569–575CrossRefPubMedGoogle Scholar
  106. 106.
    Statement of the American Society of Clinical Oncology (1996) Genetic testing for cancer susceptibility. J Clin Oncol 14:1730–1736Google Scholar
  107. 107.
    Statement of the American Society of Human Genetics (1994) Genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55:i–ivGoogle Scholar
  108. 108.
    American Society of Clinical Oncology (2003) Policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21:2397–2406CrossRefGoogle Scholar
  109. 109.
    Julian-Reynier  C et al (2009) Professionals assess the acceptablity of preimplantation genetic diagnosis and prenatal diagnosis for managing inherited predisposition to cancer. J Clin Oncol 27(27):4475–4480Google Scholar
  110. 110.
    Li FP et al (1992) Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. J Natl Cancer Inst 84:1156–1160CrossRefPubMedGoogle Scholar
  111. 111.
    Chorley W, MacDermot K (1997) Who should talk to patients with cancer about genetics? BMJ 314:441PubMedGoogle Scholar
  112. 112.
    Malkin D et al (1999) Establishment of a dedicated cancer genetics program in a tertiary pediatric centre. Am J Hum Genet 65(4):A386Google Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada

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