p53 and Hereditary Cancer

  • Diana Merino
  • David Malkin
Part of the Subcellular Biochemistry book series (SCBI, volume 85)


The roles of p53 as “guardian of the genome” are extensive, encompassing regulation of the cell cycle, DNA repair, apoptosis, cellular metabolism, and senescence - ultimately steering cells through a balance of death and proliferation. The majority of sporadic cancers exhibit loss of p53 activity due to mutations or deletions of TP53, and alterations in its signaling pathway. Germline TP53 mutations have been identified in a group of families exhibiting a rare but highly penetrant familial cancer syndrome, called the Li-Fraumeni syndrome (LFS). Between 60–80% of ‘classic’ LFS families carry mutant Trp53. The most frequent cancers observed are premenopausal breast cancer, bone and soft-tissue sarcomas, adrenal cortical carcinomas, and brain tumors. Penetrance is nearly 100% by age 70. Although TP53 is currently the only validated susceptibility locus recognized for LFS, recent studies have focused on the identification of genetic modifiers that may explain the wide phenotypic variability observed in LFS patients. Analyses of single nucleotide polymorphisms (SNPs), genome-wide copy number and telomere length have provided greater insight into the potential genetic modifiers of LFS. Moreover, the study of Trp53 mutant heterozygous mouse models has elucidated novel functions of p53, and offers insight into the mechanisms governing tumorigenesis in LFS. The key findings outlined in this chapter provide an overview of the molecular basis of LFS and the role of p53 in this unique heritable cancer syndrome.


p53 Li-Fraumeni Syndrome Cancer Predisposition Cancer Genetics 


  1. 1.
    Achatz M, Hainaut P, Ashton-Prolla P (2009) Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening? Lancet Oncol 10:920–925PubMedCrossRefGoogle Scholar
  2. 2.
    Achatz MIW, Olivier M, Le Calvez F et al (2007) The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 245:96–102. doi: 10.1016/j.canlet.2005.12.039 PubMedCrossRefGoogle Scholar
  3. 3.
    Aury-Landas J, Bougeard G, Castel H et al (2013) Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours. Eur J Hum Genet 1–8. doi:  10.1038/ejhg.2013.68
  4. 4.
    Bachinski LL, Olufemi S-E, Zhou X et al (2005) Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res 65:427–431PubMedGoogle Scholar
  5. 5.
    Baker S, Fearon E, Nigro J (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221PubMedCrossRefGoogle Scholar
  6. 6.
    Baker S, Preisinger A, Jessup J (1990) p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50:7717–7722PubMedGoogle Scholar
  7. 7.
    Barlow J, Mous M, Wiley J et al (2004) Germline BAX alterations are infrequent in Li-Fraumeni syndrome. Cancer Epidemiol Biomarkers Prev 13:1403–1406PubMedGoogle Scholar
  8. 8.
    Bell DW, Varley JM, Szydlo TE et al (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528–2531PubMedCrossRefGoogle Scholar
  9. 9.
    Birch J, Hartley A, Tricker K, Prosser J (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54:1298–1304PubMedGoogle Scholar
  10. 10.
    Birch JM, Alston RD, McNally RJ et al (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20:4621–4628. doi: 10.1038/sj.onc.1204621 PubMedCrossRefGoogle Scholar
  11. 11.
    Bond GL, Hu W, Bond EE et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602PubMedCrossRefGoogle Scholar
  12. 12.
    Bond GL, Levine AJ (2007) A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 26:1317–1323PubMedCrossRefGoogle Scholar
  13. 13.
    Bougeard G (2006) Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet 43:531–533PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Bougeard G, Limacher JM, Martin C et al (2001) Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. J Med Genet 38:253–257PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Bougeard G, Sesboue R, Baert-Desurmont S et al (2008) Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 45:535–538PubMedCrossRefGoogle Scholar
  16. 16.
    Brown LT, Sexsmith E, Malkin D (2000) Identification of a novel PTEN intronic deletion in Li-Fraumeni syndrome and its effect on RNA processing. Cancer Genet Cytogenet 123:65–68PubMedCrossRefGoogle Scholar
  17. 17.
    Burt EC, McGown G, Thorncroft M et al (1999) Exclusion of the genes CDKN2 and PTEN as causative gene defects in Li-Fraumeni syndrome. Br J Cancer 80:9–10. doi: 10.1038/sj.bjc.6690313 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Chène P (1998) In vitro analysis of the dominant negative effect of p53 mutants. J Mol Biol 281:205–209. doi: 10.1006/jmbi.1998.1897 PubMedCrossRefGoogle Scholar
  19. 19.
    Cheng J, Haas M (1990) Frequent mutations in the p53 tumor suppressor gene in human leukemia T-cell lines. Mol Cell Biol 10:5502–5509. doi: 10.1128/MCB.10.10.5502.Updated PubMedCentralPubMedGoogle Scholar
  20. 20.
    Chompret A, Abel A, Stoppa-Lyonnet D et al (2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43–47PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Costa S, Pinto D, Pereira D et al (2008) Importance of TP53 codon 72 and intron 3 duplication 16 bp polymorphisms in prediction of susceptibility on breast cancer. BMC Cancer 8:32PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Cybulski C, Masojc B, Oszutowska D et al (2008) Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers. Carcinogenesis 29:762–765. doi: 10.1093/carcin/bgn044 PubMedCrossRefGoogle Scholar
  23. 23.
    Diller L, Kassel J, Nelson C (1990) p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol. doi:  10.1128/MCB.10.11.5772. Updated
  24. 24.
    Donehower L, Harvey M, Slagle B (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366):215–221PubMedCrossRefGoogle Scholar
  25. 25.
    Donehower L, Lozano G (2009) 20 years studying p53 functions in genetically engineered mice. Nat Rev Cancer 9:831–841PubMedCrossRefGoogle Scholar
  26. 26.
    Eeles RA (1995) Germline mutations in the TP53 gene. Cancer Surv 25:101–124PubMedGoogle Scholar
  27. 27.
    Fang S, Krahe R, Lozano G et al (2010) Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations. PLoS One 5:e10813. doi: 10.1371/journal.pone.0010813 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Figueiredo BC, Sandrini R, Zambetti GP et al (2006) Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 43:91–96. doi: 10.1136/jmg.2004.030551 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Garritano S, Gemignani F, Palmero EI 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. Hum Mutat 31:143–150PubMedCrossRefGoogle Scholar
  30. 30.
    Gemignani F, Moreno V, Landi S et al (2004) A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene 23:1954–1956. doi: 10.1038/sj.onc.1207305 PubMedCrossRefGoogle Scholar
  31. 31.
    Grochola LF, Zeron-Medina J, Mériaux S, Bond GL (2010) Single-nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb Perspect Biol 2:a001032PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Harvey M, McArthur M, Montgomery C (1993) Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet 5:225–229PubMedCrossRefGoogle Scholar
  33. 33.
    Hastings PJ, Ira G, Lupski JR (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5:e1000327. doi: 10.1371/journal.pgen.1000327 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10:551–564. doi: 10.1038/nrg2593 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Hrstka R, Beranek M, Klocova K et al (2009) Intronic polymorphisms in TP53 indicate lymph node metastasis in breast cancer. Hum Mutat 11951:1205–1211. doi: 10.3892/or Google Scholar
  36. 36.
    Kemp C, Donehower L, Bradley A, Balmain A (1993) Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74:813–822PubMedCrossRefGoogle Scholar
  37. 37.
    Kuperwasser C, Hurlbut G (2000) Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice a model for Li-Fraumeni syndrome. Am J Pathol 157:2151–2159PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Lang GA, Iwakuma T, Suh Y-A et al (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861–872PubMedCrossRefGoogle Scholar
  39. 39.
    Lavigueur A, Maltby V (1989) High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9:3982–3991. doi: 10.1128/MCB.9.9.3982.Updated PubMedCentralPubMedGoogle Scholar
  40. 40.
    Li F, Fraumeni J (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Ann Intern Med 71(4):747–752PubMedCrossRefGoogle Scholar
  41. 41.
    Li F, Fraumeni J, Mulvihill J (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362PubMedGoogle Scholar
  42. 42.
    Liu G, McDonnell TJ, de Oca M, Luna R et al (2000) High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci U S A 97:4174–4179PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Liu G, Parant JM, Lang G et al (2004) Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36:63–68. doi: 10.1038/ng1282 PubMedCrossRefGoogle Scholar
  44. 44.
    Lynch H, Mulcahy G, Harris R et al (1978) Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer 41:2055–2064PubMedCrossRefGoogle Scholar
  45. 45.
    Mai PL, Malkin D, Garber JE et al (2012) Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet 205:479–487. doi: 10.1016/j.cancergen.2012.06.008 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Malkin D (2011) Li-fraumeni syndrome. Genes Cancer 2:475–484. doi: 10.1177/1947601911413466 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    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 250:1233–1238PubMedCrossRefGoogle Scholar
  48. 48.
    Marcel V, Hainaut P (2009) P53 isoforms – a conspiracy to kidnap P53 tumor suppressor activity? Cell Mol Life Sci 66:391–406. doi: 10.1007/s00018-008-8336-3 PubMedCrossRefGoogle Scholar
  49. 49.
    Marcel V, Palmero EI, Falagan-Lotsch P 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 46:766–772. doi: 10.1136/jmg.2009.066704 PubMedCrossRefGoogle Scholar
  50. 50.
    Meijers-Heijboer H, van den Ouweland A, Klijn J et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK21100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59. doi: 10.1038/ng879 PubMedCrossRefGoogle Scholar
  51. 51.
    Nichols K, Malkin D, Garber J (2001) Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 10:83–87PubMedGoogle Scholar
  52. 52.
    Nigro J, Baker S, Preisinger A (1989) Mutations in the p53 gene occur in diverse human tumor types. Nature 342:705–708PubMedCrossRefGoogle Scholar
  53. 53.
    Olive KP, Tuveson DA, Ruhe ZC et al (2004) Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119:847–860. doi: 10.1016/j.cell.2004.11.004 PubMedCrossRefGoogle Scholar
  54. 54.
    Olivier M, Goldgar DE, Sodha N et al (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63:6643–6650PubMedGoogle Scholar
  55. 55.
    Petitjean A, Achatz MIW, Borresen-Dale AL et al (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26:2157–2165. doi: 10.1038/sj.onc.1210302 PubMedCrossRefGoogle Scholar
  56. 56.
    Petitjean A, Mathe E, Kato S (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28:622–629. doi: 10.1002/humu PubMedCrossRefGoogle Scholar
  57. 57.
    Portwine C (2000) Absence of germline p16INK4a alterations in p53 wild type Li-Fraumeni syndrome families. J Med Genet 37(e13):1–4. doi: 10.1136/jmg.37.8.e13 Google Scholar
  58. 58.
    Quesnel S, Verselis S, Portwine C et al (1999) p53 compound heterozygosity in a severely affected child with Li-Fraumeni syndrome. Oncogene 18:3970–3978. doi: 10.1038/sj.onc.1202783 PubMedCrossRefGoogle Scholar
  59. 59.
    Rangarajan A, Weinberg RA (2003) Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959. doi: 10.1038/nrc1235 PubMedCrossRefGoogle Scholar
  60. 60.
    Ribeiro R, Sandrini F (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci 98:9330–9335. doi: 10.1073/pnas.161479898 PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Ruijs MWG, Schmidt MK, Nevanlinna H et al (2007) The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li–Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15:110–114PubMedCrossRefGoogle Scholar
  62. 62.
    Ruijs MWG, Verhoef S, Rookus MA et al (2010) TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet 47:421–428PubMedCrossRefGoogle Scholar
  63. 63.
    Serrano M, Lin A, McCurrach M et al (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16 INK4a. Cell 88:593–602PubMedCrossRefGoogle Scholar
  64. 64.
    Shaw P, Bovey R, Tardy S et al (1992) Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci 89:4495–4499. doi: 10.1073/pnas.89.10.4495 PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Shlien A, Tabori U, Marshall CR et al (2008) Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci U S A 105:11264–11269PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Sodha N, Williams R, Mangion J et al (2000) Screening hCHK2 for mutations. Science 289:359PubMedCrossRefGoogle Scholar
  67. 67.
    Stone J, Eeles RA, Sodha N et al (1999) Analysis of Li-Fraumeni syndrome and Li-Fraumeni-like families for germline mutations in Bcl10. Cancer Lett 147:181–185PubMedCrossRefGoogle Scholar
  68. 68.
    Tabori U, Nanda S, Druker H et al (2007) Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res 67:1415–1418. doi: 10.1158/0008-5472.CAN-06-3682 PubMedCrossRefGoogle Scholar
  69. 69.
    Tinat J, Bougeard G, Baert-Desurmont S et al (2009) 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27:e108–e109. doi: 10.1200/JCO.2009.22.7967 PubMedCrossRefGoogle Scholar
  70. 70.
    Trkova M, Hladikova M, Kasal P et al (2002) Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome? J Hum Genet 47:381–386. doi: 10.1007/s100380200055 PubMedCrossRefGoogle Scholar
  71. 71.
    Trkova M, Prochazkova K, Krutilkova V 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 110:694–702. doi: 10.1002/cncr.22834 PubMedCrossRefGoogle Scholar
  72. 72.
    Vahteristo P, Bartkova J, Eerola H et al (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432–438. doi: 10.1086/341943 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Vahteristo P, Tamminen A, Karvinen P et al (2001) p53, CHK 2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome : further evidence of CHK2 in inherited cancer predisposition. Cancer Res 61:5718–5722PubMedGoogle Scholar
  74. 74.
    Varley JM, Attwooll C, White G et al (2001) Characterization of germline TP53 splicing mutations and their genetic and functional analysis. Oncogene 20:2647–2654. doi: 10.1038/sj.onc.1204369 PubMedCrossRefGoogle Scholar
  75. 75.
    Varley JM, Thorncroft M, McGown G et al (1997) A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. Oncogene 14:865–871PubMedCrossRefGoogle Scholar
  76. 76.
    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 J 17:4657–4667PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Vousden KH, Ryan KM (2009) P53 and metabolism. Nat Rev Cancer 9:691–700. doi:10.1038/nrc2715PubMedCrossRefGoogle Scholar
  78. 78.
    Wang P-Y, Ma W, Park J-Y et al (2013) Increased oxidative metabolism in the Li–Fraumeni syndrome. New Engl J Med 368:1027–1032. doi: 10.1056/NEJMoa1214091 PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Wang Y, Blandino G, Oren M, Givol D (1998) Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs. Oncogene 1299:1923–1930CrossRefGoogle Scholar
  80. 80.
    Wolf D, Rotter V (1985) Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc Natl Acad Sci 82:790–794PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Program in Genetics and Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Departments of Pediatrics and Medical BiophysicsUniversity of TorontoTorontoCanada

Personalised recommendations