Advertisement

Li–Fraumeni syndrome heterogeneity

  • P. GargalloEmail author
  • Y. Yáñez
  • V. Segura
  • A. Juan
  • B. Torres
  • J. Balaguer
  • S. Oltra
  • V. Castel
  • A. Cañete
Review Article
  • 16 Downloads

Abstract

Clinical variability is commonly seen in Li–Fraumeni syndrome. Phenotypic heterogeneity is present among different families affected by the same pathogenic variant in TP53 gene and among members of the same family. However, causes of this huge clinical spectrum have not been studied in depth. TP53 type mutation, polymorphic variants in TP53 gene or in TP53-related genes, copy number variations in particular regions, and/or epigenetic deregulation of TP53 expression might be responsible for clinical heterogeneity. In this review, recent advances in the understanding of genetic and epigenetic aspects influencing Li–Fraumeni phenotype are discussed.

Keywords

Li–Fraumeni syndrome Genotype Phenotype Epigenome Pediatrics 

Abbreviations

LFS

Li–Fraumeni syndrome

LFL

Li–Fraumeni-like

NGS

Next-generation sequencing

CNV

Copy number variations

WGS

Whole-genome sequencing

Notes

Compliance with ethical standards

Conflict of interest

The authors declare to have no conflict of interest.

Ethical approval

This work is not a research involving human participants and/or animals.

Informed consent

Not applicable.

References

  1. 1.
    Guha T, Malkin D. Inherited TP53 mutations and the Li-Fraumeni Syndrome. Cold Spring Harb Perspect Med. 2017;7(4):1–12.CrossRefGoogle Scholar
  2. 2.
    Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Ann Intern Med. 1969;71(4):747–52.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Xie Y, Zhao WH, Hua Y, Sun Q, Wu PH. A rhabdomyosarcoma patient from a Li-Fraumeni syndrome family: a case report and literature review. Zhongguo Dang Dai ErKeZaZhi. 2017;19(12):1263–6.Google Scholar
  4. 4.
    Hettmer S, Archer NM, Somers GR, Novokmet A, Wagers AJ, Diller L, et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014;120(7):1068–75.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Mirabello L, Yeager M, Mai PL, Gastier-Foster JM, Gorlick R, Khanna C, et al. Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst. 2015;107(7):1–4.CrossRefGoogle Scholar
  6. 6.
    Ribi S, Baumhoer D, Lee K, Teo AS, Madan B, et al. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. Oncotarget. 2015;6(10):7727–40.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Arcand SL, Akbari MR, Mes-Masson AM, Provencher D, Foulkes WD, Narod SA, et al. Germline TP53 mutational spectrum in French Canadians with breast cancer. BMC Med Genet. 2015;16:24.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ginsburg OM, Akbari MR, Aziz Z, Young R, Lynch H, Ghadirian P, et al. The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. FamCancer. 2009;8(4):563–7.Google Scholar
  9. 9.
    Porter CC. Germ line mutations associated with leukemias. Hematol Am SocHematolEduc Program. 2016;2016(1):302–8.Google Scholar
  10. 10.
    Powell BC, Jiang L, Muzny DM, Treviño LR, Dreyer ZE, Strong LC, et al. Identification of TP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing. Pediatr Blood Cancer. 2013;60(6):1–3.CrossRefGoogle Scholar
  11. 11.
    Libé R, Bertherat J. Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol. 2005;153(4):477–87.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation-carriers in the NCI LFS cohort. Cancer. 2016;122(23):3673–81.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Li X, Kang J, Pan Q, Sikora-Wohlfeld W, Zhao D, Meng C, et al. Genetic analysis in a patient with nine primary malignant neoplasms: a rare case of Li-Fraumeni syndrome. Oncol Rep. 2016;35(3):1519–28.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Etzold A, Schröder JC, Bartsch O, Zechner U, Galetzka D. Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li-Fraumeni syndrome. Fam Cancer. 2015; 14(1):161–5.CrossRefGoogle Scholar
  15. 15.
    Macedo GS, Araujo Vieira I, Brandalize AP, Giacomazzi J, Inez Palmero E, Volc S. Rare germline variant (rs78378222) in the TP53 3′ UTR: evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome. Cancer Genet. 2016;209(3):97–106.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Siddiqui R, Onel K, Facio F, Nafa K, Diaz LR, Kauff N. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam Cancer. 2005;4(2):177–81.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Varley J. TP53, hChk2, and the Li-fraumenisyndrome. Methods Mol Biol. 2003;222:117–29.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Altonen LA, et al. p53, CHK2, and CHK1 genes in finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001;61(15):5718–22.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Manoukian S, Peissel B, Frigerio S, Lecis D, Bartkova J, Roversi G, et al. Two new CHEK2 germline variants detected in breast cancer/sarcoma families negative for BRCA1, BRCA2, and TP53 gene mutations. Breast Cancer Res Treat. 2011;130(1):207–15.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Ruijs MW, Broeks A, Menko FH, Ausems MG, Wagner A, Oldenburg R, et al. The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype. Hered Cancer Clin Pract. 2009;7(1):4.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Calvete O, Martinez P, Garcia-Pavia P, Benitez-Buelga C, Paumard-Hernández B, Fernandez V, et al. A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li–Fraumeni-like families. Nat Commun. 2015;6:8383.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Calvete O, Garcia-Pavia P, Domínguez F, Bougeard G, Kunze K, Braeuninger A, et al. The wide spectrum of POT1 gene variants correlates with multiple cancer types. Eur J Hum Genet. 2017;25(11):1278–81.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Barlow JW, Mous M, Wiley JC, Varley JM, Lozano G, Strong LC, et al. Germline BAX alterations are infrequent in Li-Fraumeni syndrome cancer. Epidemiol Biomarkers Prev. 2004;13(8):1403–6.Google Scholar
  24. 24.
    Andrade RC, Dos Santos AC, de Aguirre Neto JC, Nevado J, Lapunzina P, Vargas FR. TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes. Fam Cancer. 2017;16(2):243–8.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Brown LT, Sexsmith E, Malkin D. Identification of a novel PTEN intronic deletion in Li-Fraumeni syndrome and its effect on RNA processing. Cancer Genet Cytogenet. 2000;123(1):65–8.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Basso TR, Villacis RA, Canto LM, Alves VM, Lapa RM, Nóbrega AF, et al. Genomic profile of a Li-Fraumeni-like syndrome patient with a 45, X/46, XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome. Cancer Genet. 2015;208(6):341–4.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Yamada H, Shinmura K, Yamamura Y, Kurachi K, Nakamura T, Tsuneyoshi T, et al. Identification and characterization of a novel germline p53 mutation in a patient with glioblastoma and colon cancer. Int J Cancer. 2009;125(4):973–6.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Pal T, Brzosowicz J, Valladares A, Wiesner GL, Laronga C. Identification and management of TP53 gene carriers detected through multigene panel testing. South Med J. 2017;110(10):643–8.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Cao AY, Jin W, Shi PC, Di GH, Shen ZZ, Shao ZM. Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population. Breast Cancer Res Treat. 2010;119(2):295–303.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Peng G, Bojadzieva J, Ballinger ML, Li J, Blackford AL, Mai PL, et al. Estimating TP53 mutation carrier probability in families with Li-Fraumeni syndrome using LFSPRO. Cancer Epidemiol Biomarkers Prev. 2017;26(6):837–44.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, et al. Relative frequency and morphology of cancers in carriers of germline TP53 Mutations. Oncogene. 2001;20(34):4621–8.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Custodio G, Taques GR, Figueiredo BC, Gugelmin ES, Oliveira Figueiredo MM, Watanabe F, et al. Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in Southern Brazil. PLoS One. 2011;6(3):e18015.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Giavedoni P, Ririe M, Carrera C, Puig S, Malvehy J. Familial melanoma associated with Li-Fraumeni syndrome and atypical mole syndrome: total-body digital photography, dermoscopy and confocal microscopy. Acta DermVenereol. 2017;97(6):720–3.Google Scholar
  34. 34.
    Krześniak M, Butkiewicz D, Rachtan J, Matuszczyk I, Grzybowska E, Rusin MA. Novel germline TP53 mutation p.Pro190Arg detected in a patient with lung and bilateral breast cancers. Adv Med Sci. 2017;62(2):207–10.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Chang VY, Federman N, Martinez-Agosto J, Tatishchev SF, Nelson SF. Whole exome sequencing of pediatric gastric adenocarcinoma reveals an atypical presentation of Li-Fraumeni syndrome. Pediatr Blood Cancer. 2013;60(4):570–4.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Andrade KC, Kowalski LP, Achatz MI. Frequency of thyroid carcinoma in Brazilian TP53 p.R337H carriers with Li Fraumeni syndrome. JAMA Oncol. 2017;3(10):1400–2.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, et al. Hereditary ovarian cancer: not only BRCA1 and 2 genes. Biomed Res Int. 2015;2015:341723.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Yurgelun MB, Masciari S, Joshi VA, Mercado RC, Lindor NM, Gallinger S, et al. GermlineTP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry. JAMA Oncol. 2015;1(2):214–21.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Valdez JM, Nichols KE, Kesserwan C. Li-Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition. Br J Haematol. 2017;176(4):539–52.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gargallo P, Segura V, Yáñez Y, Balaguer J, Cañete A. Li-Fraumeni: ¿la detección de familias aumentaría la supervivencia entre sus miembros? Anales de Pediatría. 2018;90(1):54–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Bougeard G, Renaux-Petel M, Flaman J-M, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345–52.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27:1250–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Nichols KE, Malkin D, Garber JE, Fraumeni JF, Li FP. Germline p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001;10:83–7.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Ruijs MW, Verhoef S, Rookus MA, et al. 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. 2010;47:421–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring HarbPerspect Med. 2016;6(5):1–16.Google Scholar
  46. 46.
    Zerdoumi Y, Lanos R, Raad S, Flaman JM, Bougeard G, Frebourg T, et al. Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. Hum Mol Genet. 2017;26(14):2812.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Merino D, Malkin D. p53 and hereditary cancer. Subcell Biochem. 2014;85:1–16.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Soussi T, Wiman KG. TP53: an oncogene in disguise. Cell Death Differ. 2015;22(8):1239–49.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Sabapathy K. The contrived mutant p53 oncogene—beyond loss of functions. Front Oncol. 2015;5:276.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ferraiuolo M, Verduci L, Blandino G, Strano S. Mutant p53 protein and the hippo transducers YAP and TAZ: a critical oncogenic node in human cancers. Int J Mol Sci. 2017;18(5):1–29.Google Scholar
  51. 51.
    Rufini A, Tucci P, Celardo I, et al. Senescence and aging: the critical roles of p53. Oncogene. 2013;32(43):5129–43.PubMedCrossRefGoogle Scholar
  52. 52.
    Sahin E, De Pinho RA. Axis of ageing: telomeres, p53 and mitochondria. Nat Rev MolCell Biol. 2012;13(6):397–404.CrossRefGoogle Scholar
  53. 53.
    Wang SJ, Gu W. To be, or not to be: functional dilemma of p53 metabolic regulation. Curr Opin Oncol. 2014;26(1):78–85.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Cheung EC, Vousden KH. The role of p53 in glucose metabolism. Curr Opin Cell Biol. 2010;22(2):186–91.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhuang J, Ma W, Lago CU, et al. Metabolic regulation of oxygen and redox homeostasis by p53: lessons from evolutionary biology? Free Radical Bio Med. 2012;53(6):1279–85.CrossRefGoogle Scholar
  56. 56.
    Menendez D, Shatz M, Resnick MA. Interactions between the tumor suppressor p53 and immune responses. Curr Opin Oncol. 2013;25(1):85–92.PubMedCrossRefGoogle Scholar
  57. 57.
    Iannello A, Thompson TW, Ardolino M, et al. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med. 2013;210(10):2057–69.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kamada R, Toguchi Y, Nomura T, Imagawa T, Sakaguchi K. Tetramer formation of tumor suppressor protein p53: structure, function, and applications. Biopolymers. 2016;106(4):598–612.PubMedCrossRefGoogle Scholar
  59. 59.
    Demir Ö, Ieong PU, Amaro RE. Full-length p53 tetramer bound to DNA and its quaternary dynamics. Oncogene. 2017;36(10):1451–60.PubMedCrossRefGoogle Scholar
  60. 60.
    Fischer M, Steiner L, Engeland K. The transcription factor p53: not a repressor, solely an activator. Cell Cycle. 2014;13(19):3037–58.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Blagosklonny MV. P53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect. FASEB J. 2000;14:1901–7.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer. 2011;2(4):466–74.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Walerych D, Napoli M, Collavin L, Del Sal G. The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis. 2012;33(11):2007–17.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25(3):304–17.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Leroy B, Anderson M, Soussi T. TP53mutations in human cancer: database reassessment and prospects for the next decade. Hum Mutat. 2014;35(6):672–88.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Zhou X, Hao Q, Lu H. Mutant p53 in cancer therapy—the barrier or the path. J Mol Cell Biol. 2019;11(4):293–305.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Dridi W, Krabchi K, Gadji M, Lavoie J, Bronsard M, Fetni R, Drouin R. Dominant negative activity of mutated p53proteins. Med Sci (Paris). 2006;22(3):301–7.CrossRefGoogle Scholar
  68. 68.
    Xu J, Qian J, Hu Y, Wang J, Zhou X, Chen H, Fang JY. Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. Sci Rep. 2014;4:4223.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Zerdoumi Y, Aury-Landas J, Bonaïti-Pellié C, Derambure C, Sesboüé R, Renaux-Petel M, et al. Drastic effect of germline TP53 missense mutations in Li-Fraumenipatients. Hum Mutat. 2013;34(3):453–61.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Nichols KE, Malkin D. Genotype versus phenotype: the yin and yang of germline TP53 mutations in Li-Fraumeni syndrome. J Clin Oncol. 2015;33(21):2331–3.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Amadou A, Waddington Achatz MI, Hainaut P. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. Curr Opin Oncol. 2018;30(1):23–9.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline. Mutation Carriers Cancer. 2012;118(5):1387–96.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63(20):6643–50.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Id Said B, Kim H, Tran J, Novokmet A, Malkin D. Super-transactivation TP53 variant in the germline of a family with Li-Fraumeni syndrome. Hum Mutat. 2016;37(9):889–92.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Marcel V, Palmero EI, Falagan-Lotsch P, Martel-Planche G, Ashton-Prolla P, Olivier M. TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. J Med Genet. 2009;46(11):766–72.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Sagne C, Marcel V, Bota M, Martel-Planche G, Nobrega A, Palmero EI, et al. Age at cancer onset in germline TP53 mutation carriers: association with polymorphisms in predicted G-quadruplex structures. Carcinogenesis. 2014;35(4):807–15.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet. 2006;43(6):531–3.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomäki K, Pruntel R. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet. 2007;15(1):110–4.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Macedo GS, Vieira IA, Vianna FSL, Alemar B, Giacomazzi J, Brandalize APC, et al. P53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers. Fam Cancer. 2018;17(2):269–74.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Renaux-Petel M, Sesboüé R, Baert-Desurmont S, Vasseur S, Fourneaux S, Bessenay E, et al. The MDM2 285G-309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome. Fam Cancer. 2014;1:127–30.CrossRefGoogle Scholar
  81. 81.
    Xiao J, Lin H, Luo X, Luo X, Wang Z. miR-605 joins p53 network to form a p53:miR-605:Mdm2 positive feedback loop in response to stress. EMBO J. 2011;30(3):524–32.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Id Said B, Malkin D. A functional variant in miR-605 modifies the age of onset in Li-Fraumeni syndrome. Cancer Genet. 2015;208(1–2):47–51.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Rokavec M, Li H, Jiang L, Hermeking H. The p53/miR-34 axis in development and disease. J Mol Cell Biol. 2014;6(3):214–30.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Samuel N, Wilson G, Lemire M, Id Said B, Lou Y, Li W, et al. Genome-wide DNA methylation analysis reveals epigenetic dysregulation of microRNA-34A in TP53-associated cancer susceptibility. J Clin Oncol. 2016;34(30):3697–704.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Eyfjord JE, et al. TP53 abnormalities and genetic instability in breast cancer. Acta Oncol. 1995;34:663–7.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Georgiades IB, Curtis LJ, Morris RM, Bird CC, Wyllie AH. Heterogeneity studies identify a subset of sporadic colorectal cancers without evidence for chromosomal or microsatellite instability. Oncogene. 1999;18:7933–40.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Primdahl H, et al. Allelic imbalances in human bladder cancer: genome-wide detection with high-density single-nucleotide polymorphism arrays. J Natl Cancer Inst. 2002;94:216–23.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Shlien A, Tabori U, Marshall CR, Pienkowska M, Feuk L, Novokmet A. Excessive genomic DNA copy number variation in the Li Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci USA. 2008;105(32):11264–9.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Ariffin H, Chan AS, Oh L, Abd-Ghafar S, Ong GB, Mohamed M, et al. Frequent occurrence of gastric cancer in Asian kindreds with Li–Fraumeni syndrome. Clin Genet. 2015;88(5):450–5.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Silva AG, Achatz IM, Krepischi AC, Pearson PL, Rosenberg C. Number of rare germline CNVs and TP53 mutation types. Orphanet J Rare Dis. 2012;7:101.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kruk PA, Bohr VA. Telomeric length in individuals and cell lines with altered p53 status. RadiatOncol Investig. 1999;7:13–21.Google Scholar
  92. 92.
    Bekaert S, Derradji H, Meyer TD, et al. Telomere shortening is associated with malformation in p53-deficient mice after irradiation during specific stages of development. DNA Repair. 2005;4:1028–37.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Stansel RM, Subramanian D, Griffith JD. p53 binds telomeric single strand overhangs and t-loop junctions in vitro. J Biol Chem. 2002;277:11625–8.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Trkova M, Prochazkova K, Krutilkova V, Sumerauer D, Sedlacek Z. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007;110(3):694–702.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Tabori U, Nanda S, Druker H, Lees J, Malkin D. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. 2007;67(4):1415–8.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Macedo GS, Lisbôa da Motta L, Giacomazzi J, Netto CB, Manfredini V, Vanzin CS, et al. Increased oxidative damage in carriers of the germline TP53 p.R337H mutation. PLoS One. 2012; 7(10):e47010.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Saldaña-Meyer R, Recillas-Targa F. Transcriptional and epigenetic regulation of the p53 tumor suppressor gene. Epigenetics. 2011;6(9):1068–77.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009;137(7):1194–211.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Fortes FP, Kuasne H, Marchi FA, Miranda PM, Rogatto SR, Achatz MI. DNA methylation patterns of candidate genes regulated by thymine DNA glycosylase in patients with TP53 germline mutations. Braz J Med Biol Res. 2015;48(7):610–5.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, et al. Functional interaction of p53 and BLM DNA helicase in apoptosis. J Biol Chem. 2001;276(35):32948–55.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Trkova M, Hladikova M, Kasal P, Goetz P, Sedlacek Z. Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome? J Hum Genet. 2002;47(8):381–6.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet. 2005;118(3–4):489–98.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Ariffin H, Hainaut P, Puzio-Kuter A, Choong SS, Chan AS, Tolkunov D, et al. Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci USA. 2014;111(43):15497–501.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Franceschi S, Spugnesi L, Aretini P, Lessi F, Scarpitta R, Galli A. Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile. Carcinogenesis. 2017;38(9):938–43.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  1. 1.Pediatric OncologyLa Fe HospitalValenciaSpain
  2. 2.Clinical and Translational Oncology Research GroupLa Fe HospitalValenciaSpain
  3. 3.Genetics UnitLa Fe HospitalValenciaSpain
  4. 4.Genetics DepartmentValencia UniversityValenciaSpain

Personalised recommendations