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Li-Fraumeni syndrome: cancer risk assessment and clinical management

Nature Reviews Clinical Oncology volume 11, pages 260–271 (2014)Cite this article

Subjects

Key Points

  • Inherited cancer predisposition syndromes are increasingly diagnosed due to greater public awareness of germline genetic testing, and also as an incidental finding when somatic mutation testing for 'druggable targets'

  • Some inherited cancer syndromes predispose to cancers at multiple sites, such as Li-Fraumeni syndrome (LFS) caused by germline TP53 mutations, requiring a whole-body approach to cancer risk management

  • The 5-year, 10-year and lifetime cancer risk of many the LFS-associated cancers remains unclear and further study is required to provide such data, which can guide cancer risk management

  • At present, a limited number of validated screening tests for LFS-associated cancers exist, and no validated screening tests have been studied specifically in people with LFS

  • Prospective trials studying the utility and the psychosocial effects of a whole-body approach to screening in LFS are in progress

  • A pragmatic schedule for a whole-body approach to screening is proposed while the results of the prospective trials are awaited

Abstract

Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.

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References

  1. Pruthi, S., Gostout, B. S. & Lindor, N. M. Identification and management of women with BRCA mutations or hereditary predisposition for breast and ovarian Cancer. Mayo Clin. Proc. 85, 1111–1120 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vasen, H. F. et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62, 812–823 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Li, F. P. et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 48, 5358–5362 (1988).

    CAS  PubMed  Google Scholar 

  4. Birch, J. M. et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 54, 1298–1304 (1994).

    CAS  PubMed  Google Scholar 

  5. Garber, J. E. et al. Follow up study of 24 families with Li-Fraumeni syndrome. Cancer Res. 51, 6094–6097 (1991).

    CAS  PubMed  Google Scholar 

  6. Birch, J. M. et al. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene 17, 1061–1068 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Ruijs, M. W. 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. 47, 421–428 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Olivier, M., Hollstein, M. & Hainaut, P. TP53 Mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mai, P. L. et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 205, 479–487 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Varley, J. M. et al. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. 57, 3245–3252 (1997).

    CAS  PubMed  Google Scholar 

  12. Hwang, S. J., Lozano, G., Amos, C. I. & Strong, L. C. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am. J. Hum. Genet. 72, 975–983 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lustbader, E. D., Williams, W. R., Bondy, M. L., Strom, S. & Strong, L. C. Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients. Am. J. Hum. Genet. 51, 344–356 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Schneider, K., Zelley, K., Nichols, K. E. & Garber, J. GeneReviews: Li-Fraumeni Syndrome (eds Pagon, R. A. et al. University of Washington, 1999).

    Google Scholar 

  15. Chompret, A. et al. p53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer 82, 1932–1937 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cancer Institute NSW. eviQ Cancer Treatments Online [online], (2013).

  17. Olivier, M. et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 63, 6643–6650 (2003).

    CAS  PubMed  Google Scholar 

  18. Mitchell, G. et al. High Frequency of Germline TP53 mutations in a prospective adult-onset sarcoma cohort. PLoS ONE 8, e69026 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eeles, R. A. Germline mutations in the TP53 gene. Cancer Surv. 25, 101–124 (1995).

    CAS  PubMed  Google Scholar 

  20. Tinat, J. et al. 2009 version of the Chompret criteria for Li-Fraumeni syndrome. J. Clin. Oncol. 27, E108–E109 (2009).

    Article  PubMed  Google Scholar 

  21. Sorrell, A. D., Espenschied, C. R., Culver, J. O. & Weitzel, J. N. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome: current status of clinical applications and future directions. Mol. Diagn. Ther. 17, 31–47 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wu, C. C., Shete, S., Amos, C. I. & Strong, L. C. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res. 66, 8287–8292 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Malkin, D. Li-Fraumeni syndrome. Genes Cancer 2, 475–484 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ognjanovic, S., Olivier, M., Bergemann, T. L. & Hainaut, P. Sarcomas in TP53 germline mutation carriers a review of the IARC TP53 database. Cancer 118, 1387–1396 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Petitjean, A. et al. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Masciari, S. et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res. Treat. 133, 1125–1130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tabori, U. et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J. Clin. Oncol. 28, 1995–2001 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Villani, A. et al. Striking survival benefit with early detection of brain tumors for children with Li-Fraumeni syndrome. Neuro-Oncology 12, ii35–ii36 (2010).

    Google Scholar 

  29. Wong, P. et al. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology 130, 73–79 (2006).

    Article  PubMed  Google Scholar 

  30. Masciari, S. et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet. Med. 13, 651–657 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nichols, K. E., Malkin, D., Garber, J. E., Fraumeni, J. F. & Li, F. P. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol. Biomarkers Prev. 10, 83–87 (2001).

    CAS  PubMed  Google Scholar 

  32. Birch, J. M. et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20, 4621–4628 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Gonzalez, K. D. et al. Beyond Li-Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J. Clin. Oncol. 26, 1250–1256 (2008).

    Google Scholar 

  34. Hisada, M., Garber, J. E., Fung, C. Y., Fraumeni, J. F. & Li, F. P. Multiple primary cancers in families with Li-Fraumeni syndrome. J. Natl Cancer Inst. 90, 606–611 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Ross, J. A. Multiple malignancies in Li-Fraumeni syndrome: younger age at first onset the strongest predictor. Med. Pediatr. Oncol. 33, 108–109 (1999).

    Article  Google Scholar 

  36. Ferrarini, A. et al. Early occurrence of lung adenocarcinoma and breast cancer after radiotherapy of a chest wall sarcoma in a patient with a de novo germline mutation in TP53. Fam. Cancer 10, 187–192 (2011).

    Article  PubMed  Google Scholar 

  37. Henry, E. et al. Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome. J. Natl Compr. Canc. Netw. 10, 939–942 (2012).

    Article  PubMed  Google Scholar 

  38. Heymann, S. et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat. Oncol. 5, 104 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Limacher, J. M., Frebourg, T., Natarajan-Ame, S. & Bergerat, J. P. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int. J. Cancer 96, 238–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Salmon, A. et al. Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline 'de-novo' TP53 mutation. Clin. Oncol. 19, 490–493 (2007).

    Article  CAS  Google Scholar 

  41. Kemp, C. J., Wheldon, T. & Balmain, A. p53 deficient mice are extremely susceptible to radiotion-induced tumorigenesis. Nat. Genet. 8, 66–69 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Hwang, S. J. et al. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum. Genet. 113, 238–243 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Brosh, R. & Rotter, V. When mutants gain new powers: news from the mutant p53 field. Nat. Rev. Cancer 9, 701–713 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. InSiGHT. International Society for Gastrointestinal Hereditary Tumours [online], (2008).

  45. ENIGMA. Evidence-based Network for the Interpretation of Germline Mutant Alleles [online], (2013).

  46. Kato, S. et al. Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc. Natl Acad. Sci. USA 100, 8424–8429 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wellcome Trust Sanger Institute. COSMIC: Catologue of Somatic Mutation in Cancer [online], (2014).

  48. Koboldt, D. C. et al. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

    Article  CAS  Google Scholar 

  49. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  50. Finlay, C. A., Hinds, P. W. & Levine, A. J. The p53 proto-oncogene can act as a suppressor of transformation. Cell 57, 1083–1093 (1989).

    Article  CAS  PubMed  Google Scholar 

  51. Bond, G. L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Ruijs, M. et al. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur. J. Hum. Genet. 15, 110–114 (2006).

    Article  PubMed  CAS  Google Scholar 

  53. Bougeard, G. et al. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J. Med. Genet. 43, 531–533 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Fang, S. et al. 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 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Malkin, D. in Adrenocortical Carcinoma: Basic Science and Clinical Concepts (eds Hammer, G. D. & Else, T.), 173–191 (Springer, 2011).

    Google Scholar 

  56. Marcel, V. et al. 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Wu, C.-C. et al. Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. Hum. Genet. 129, 663–673 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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. 47, 381–386 (2002).

    Article  PubMed  Google Scholar 

  59. 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 110, 694–702 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. 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. 67, 1415–1418 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Shlien, A. et al. Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc. Natl Acad. Sci. USA 105, 11264–11269 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rausch, T. et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. American Cancer Society. Breast Cancer: Early Detection; The importance of finding breast cancer early [online], (2012).

  65. National Breast and Ovarian Cancer Centre. Early detection of breast cancer NBOCC position statement [online], (2009).

  66. Biau, D. J. et al. Local recurrence of localized soft tissue sarcoma: a new look at old predictors. Cancer 118, 5867–5877 (2012).

    Article  PubMed  Google Scholar 

  67. Novais, E. N. et al. Do surgical margin and local recurrence influence survival in soft tissue sarcomas? Clin. Orthop. Relat. Res. 468, 3003–3011 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Stefanovski, P. D. et al. Prognostic factors in soft tissue sarcomas: a study of 395 patients. Eur. J. Surg. Oncol. 28, 153–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Hottinger, A. F. & Khakoo, Y. Neurooncology of familial cancer syndromes. J. Child Neurol. 24, 1526–1535 (2009).

    Article  PubMed  Google Scholar 

  70. Majchrzak, K. et al. The assessment of prognostic factors in surgical treatment of low-grade gliomas: a prospective study. Clin. Neurol. Neurosurg. 114, 1135–1144 (2012).

    Article  PubMed  Google Scholar 

  71. Deb, P., Sharma, M. C., Mahapatra, A. K., Agarwal, D. & Sarkar, C. Glioblastoma multiforme with long term survival. Neurol. India 53, 329–332 (2005).

    Article  PubMed  Google Scholar 

  72. Krauze, A. V. et al. Prognostic factors for survival and recurrence in adult medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys. 78, S269–S269 (2010).

    Article  Google Scholar 

  73. Wrede, B., Liu, P., Ater, J. & Wolff, J. E. Second surgery and the prognosis of choroid plexus carcinoma—results of a meta-analysis of individual cases. Anticancer Res. 25, 4429–4433 (2005).

    PubMed  Google Scholar 

  74. Wolff, J. E. A., Sajedi, M., Brant, R., Coppes, M. J. & Egeler, R. M. Choroid plexus tumours. Br. J. Cancer 87, 1086–1091 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Michalkiewicz, E. et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the international pediatric adrenocortical tumor registry. J. Clin. Oncol. 22, 838–845 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Rodriguez-Galindo, C., Figueiredo, B. C., Zambetti, G. P. & Ribeiro, R. C. Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr. Blood Cancer 45, 265–273 (2005).

    Article  PubMed  Google Scholar 

  77. Schulick, R. D. & Brennan, M. F. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann. Surg. Oncol. 6, 719–726 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Custodio, G. et al. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J. Clin. Oncol. 31, 2619–2626 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Passaperuma, K. et al. Long-term results of screening with magnetic resonance imaging in women with BRCA mutations. Br. J. Cancer 107, 24–30 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rijnsburger, A. J. et al. BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC screening study. J. Clin. Oncol. 28, 5265–5273 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Clark, A. S. & Domchek, S. M. Clinical management of hereditary breast cancer syndromes. J. Mammary Gland Biol. Neoplasia 16, 17–25 (2011).

    Article  PubMed  Google Scholar 

  82. Leach, M. O. et al. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 365, 1769–1778 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Kriege, M. et al. Tumor characteristics and detection method in the MRISC screening program for the early detection of hereditary breast cancer. Breast Cancer Res. Treat. 102, 357–363 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Hendrick, R. E. Radiation doses and cancer risks from breast imaging studies. Radiology 257, 246–253 (2010).

    Article  PubMed  Google Scholar 

  85. Towler, B. et al. A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, Hemoccult. BMJ 317, 559–565 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. de Vos tot Nederveen Cappel, W. H. et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis. Colon Rectum 45, 1588–1594 (2002).

    Article  PubMed  Google Scholar 

  87. Pox, C. P. et al. Efficacy of a nationwide screening colonoscopy program for colorectal cancer. Gastroenterology 142, 1460–1472 (2012).

    Article  PubMed  Google Scholar 

  88. Kubota, H. et al. Impact of screening survey of gastric cancer on clinicopathological features and survival: retrospective study at a single institution. Surgery 128, 41–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Sereno, M. et al. Gastric tumours in hereditary cancer syndromes: clinical features, molecular biology and strategies for prevention. Clin. Transl. Oncol. 13, 599–610 (2011).

    Article  PubMed  Google Scholar 

  90. Masciari, S. et al. F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA 299, 1315–1319 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Kleinerman, R. A. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr. Radiol. 39, S27–S31 (2009).

    Article  PubMed  Google Scholar 

  92. Varley, J. M. Germline TP53 mutations and Li-Fraumeni syndrome. Hum. Mutat. 21, 313–320 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 12, 559–567 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Canto, M. I. et al. Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. Gastroenterology 142, 796–804 (2012).

    Article  PubMed  Google Scholar 

  95. Wu, N.-Y. et al. Magnetic resonance imaging for lung cancer detection: experience in a population of more than 10,000 healthy individuals. BMC Cancer 11, 242 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  96. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  97. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  98. ANZCTR: Australia New Zealand Clinical Trials Registry. Trial from ANZCTR [online], (2013).

  99. Wilson, J. M. & Jungner, G. Principles and practice of screening for disease. Bol. Oficina Sanit. Panam. 65, 281–393 (1968).

    CAS  PubMed  Google Scholar 

  100. Gray, J. A. New concepts in screening. Br. J. Gen. Pract. 54, 292–298 (2004).

    PubMed  PubMed Central  Google Scholar 

  101. Lozano, G. Mouse models of p53 functions. Cold Spring Harb. Perspect. Biol. 2, a001115 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Leone, G., Mele, L., Pulsoni, A., Equitani, F. & Pagano, L. The incidence of secondary leukemias. Haematologica 84, 937–945 (1999).

    CAS  PubMed  Google Scholar 

  103. Lammens, C. R. et al. Regular surveillance for Li-Fraumeni Syndrome: advice, adherence and perceived benefits. Fam. Cancer 9, 647–654 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hutton, J. et al. Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study. Br. J. Cancer 104, 578–586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Maheu, C. et al. Pancreatic cancer risk counselling and screening: impact on perceived risk and psychological functioning. Fam. Cancer 9, 617–624 (2010).

    Article  PubMed  Google Scholar 

  106. Gopie, J. P., Vasen, H. F. A. & Tibben, A. Surveillance for hereditary cancer: does the benefit outweigh the psychological burden?—a systematic review. Crit. Rev. Oncol. Hematol. 83, 329–340 (2012).

    Article  PubMed  Google Scholar 

  107. Cuzick, J. et al. Long-term results of tamoxifen prophylaxis for breast cancer-96-month follow-up of the randomized IBIS-I trial. J. Natl Cancer Inst. 99, 272–282 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Fisher, B. et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl Cancer Inst. 97, 1652–1662 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Tabar, L., Smith, R. A. & Duffy, S. W. Update on effects of screening mammography. Lancet 360, 337–337 (2002).

    Article  PubMed  Google Scholar 

  110. Gøtzsche, P. C. & Nielsen, M. Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews, Issue 1, Art. No.: CD001877 http://dx.doi.org/10.1002/14651858.CD001877.pub4.

  111. Domchek, S. M. et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304, 967–975 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bacci, G. et al. Predictive factors for local recurrence in osteosarcoma—540 patients with extremity tumors followed for minimum 2.5 years after neoadjuvant chemotherapy. Acta Orthop. Scand. 69, 230–236 (1998).

    Article  CAS  PubMed  Google Scholar 

  113. Andreou, D. et al. The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. Ann. Oncol. 22, 1228–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Seidinger, A. L. et al. Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. Cancer 117, 2228–2235 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Foresman, W. H. & Messing, E. M. Bladder cancer: natural history, tumor markers, and early detection strategies. Semin. Surg. Oncol. 13, 299–306 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Cappell, M. S. & Goldberg, E. S. The relationship between the clinical presentation and spread of colon cancer in 315 consecutive patients—a significant trend of earlier cancer-detection from 1982 through 1988 at a university hospital. J. Clin. Gastroenterol. 14, 227–235 (1992).

    Article  CAS  PubMed  Google Scholar 

  117. Australian Cancer Network Colorectal Cancer Guidelines Revision Committee. Clinical Practice Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer [online], (2005).

  118. Burn, J. Bowel cancer chemoprevention—ready for the clinic? Hered. Cancer Clin. Pract. 10 (Suppl. 2), A12 (2011).

    Google Scholar 

  119. Mori, Y. et al. Effect of periodic endoscopy for gastric cancer on early detection and improvement of survival. Gastric Cancer 4, 132–136 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Battisti, S., Braud, G., Rigaud, J. & Bouchot, O. Sporadic kidney cancer in patients younger than 45 [French]. Prog. Urol. 17, 934–938 (2007).

    Article  PubMed  Google Scholar 

  121. Kaste, S. et al. Wilms tumour: prognostic factors, staging, therapy and late effects. Pediatr. Radiol. 38, 2–17 (2008).

    Article  PubMed  Google Scholar 

  122. Moon, S. B., Shin, H. B., Seo, J. M. & Lee, S. K. Hepatoblastoma: 15-year experience and role of surgical treatment. J. Korean Surg. Soc. 81, 134–140 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Brown, J. et al. Pretreatment prognostic factors for children with hepatoblastoma results from the International Society of Paediatric Oncology (SIOP) Study SIOPEL 1. Eur. J. Cancer 36, 1418–1425 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Veronesi, G. et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann. Intern. Med. 157, 776–784 (2012).

    Article  PubMed  Google Scholar 

  125. Dominioni, L. et al. Stage I nonsmall cell lung carcinoma: analysis of survival and implications for screening. Cancer 89, 2334–2344 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Abe, M. et al. Malignant transformation of breast fibroadenoma to malignant phyllodes tumor: long-term outcome of 36 malignant phyllodes tumors. Breast Cancer 18, 268–272 (2011).

    Article  PubMed  Google Scholar 

  127. Tan, P. H. et al. The role of pathologic parameters. Am J. Clin. Pathol. 123, 529–540 (2005).

    Article  PubMed  Google Scholar 

  128. Masri, G. D. et al. Screening and surveillance of patients at high-risk for malignant-melanoma result in detection of earlier disease. J. Am. Acad. Dermatol. 22, 1042–1048 (1990).

    Article  CAS  PubMed  Google Scholar 

  129. van der Rhee, J. I. et al. Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families. J. Am. Acad. Dermatol. 65, 289–296 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Leiter, U. et al. Is detection of melanoma metastasis during surveillance in an early phase of development associated with a survival benefit? Melanoma Res. 20, 240–246 (2010).

    Article  PubMed  Google Scholar 

  131. Shore, R. N., Shore, P., Monahan, N. M. & Sundeen, J. Serial screening for melanoma: measures and strategies that have consistently achieved early detection and cure. J. Drugs Dermatol. 10, 244–252 (2011).

    PubMed  Google Scholar 

  132. Woodward, E. R. et al. Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective. BJOG 114, 1500–1509 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Kauff, N. D. et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J. Clin. Oncol. 26, 1331–1337 (2008).

    Article  PubMed  Google Scholar 

  134. Vasen, H. F. A. et al. Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation. Gastroenterology 140, 850–856 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Harinck, F. et al. Is early diagnosis of pancreatic cancer fiction? Surveillance of individuals at high risk for pancreatic cancer. Dig. Dis. 28, 670–678 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Mitra, A. V. et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int. 107, 28–39 (2011).

    Article  PubMed  Google Scholar 

  137. Narod, S. A. et al. The impact of family history on early detection of prostate cancer. Nat. Med. 1, 99–101 (1995).

    Article  CAS  PubMed  Google Scholar 

  138. National Comprehensive Cancer Network. NCCN guidelines of the NCCN Guidelines for Detection, Prevention & Risk Reduction; Genetic/Familial High-Risk Assessment: Breast and Ovarian [online], (2014).

  139. MDJunction. Clinical Aspects of LFS—Criteria and Screening Propositions from Around the World—Conference Summa [online], (2010).

  140. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; Colorectal Cancer Screening version 2 [online], (2013).

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Authors and Affiliations

  1. The Familial Cancer Service, Crown Princess Mary Cancer Centre, Sydney Medical School, Westmead Millennium Institute, Westmead, 2145, NSW, Australia

    Kate A. McBride & Judy Kirk

  2. Research Division, Sir Peter MacCallum Department of Oncology, University of Melbourne, Peter MacCallum Cancer Centre, East Melbourne, 3002, VIC, Australia

    Mandy L. Ballinger

  3. Sir Peter MacCallum Department of Oncology, The Familial Cancer Centre, University of Melbourne, Peter MacCallum Cancer Centre, East Melbourne, 3002, VIC, Australia

    Gillian Mitchell

  4. Medical Oncology Unit, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK

    Emma Killick

  5. Department of Cancer Medicine, Sydney Medical School, Royal Prince Alfred Hospital, Camperdown, 2040, NSW, Australia

    Martin H. N. Tattersall

  6. Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, SM2 5PT, Surrey, UK

    Rosalind A. Eeles

  7. The Kinghorn Cancer Centre and Garvan Institute, Darlinghurst, 2010, NSW, Australia

    David M. Thomas

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  1. Kate A. McBride
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  2. Mandy L. Ballinger
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  3. Emma Killick
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  6. Rosalind A. Eeles
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  7. David M. Thomas
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  8. Gillian Mitchell
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Contributions

D.M.T. and G.M. contributed equally to this Review. K.A.M. researched the data for the article. All authors contributed substantially to discussion of content, the writing of the article review and/or editing of the manuscript before submission.

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Correspondence to Gillian Mitchell.

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The authors declare no competing financial interests.

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McBride, K., Ballinger, M., Killick, E. et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol 11, 260–271 (2014). https://doi.org/10.1038/nrclinonc.2014.41

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