Abstract
Li-Fraumeni syndrome (LFS) is a rare familial cancer-predisposing syndrome, which is inherited in an autosomal dominant pattern. LFS patients often present with multiple primary tumors and an early age of onset. The lifetime risk of cancer is estimated to be 73 % for males and nearly 100 % for females. Germline mutations in the tumor suppressor gene, TP53, are associated with LFS and can be detected in more than 60 % of classic LFS families. Clinical genetic testing for TP53 is available for individuals with a suspected or known clinical diagnosis of LFS or a molecular diagnosis based on a history of an identified TP53 mutation in a family member. Although preventive and surveillance options for LFS are currently limited, presymptomatic genetic testing can provide early diagnosis of individuals at risk of cancer, closer surveillance, earlier detection, and treatment for cancers and an increased likelihood of improved outcomes.
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References
Li FP, Fraumeni Jr JF. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71(4):747–52.
Chompret A, Brugieres L, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82(12):1932–7.
Birch JM, Hartley AL, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994;54(5):1298–304.
Eeles RA. Germline mutations in the TP53 gene. Cancer Surv. 1995;25:101–24.
Petitjean A, Achatz MI, et al. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26(15):2157–65.
Petitjean A, Mathe E, 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. 2007;28(6):622–9.
Lustbader ED, Williams WR, et al. Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients. Am J Hum Genet. 1992;51(2):344–56.
Gonzalez KD, Noltner KA, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27(8):1250–6.
Gonzalez KD, Buzin CH, et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009;46:689–93.
Varley JM, Evans DG, et al. Li-Fraumeni syndrome–a molecular and clinical review. Br J Cancer. 1997;76(1):1–14.
Chompret A et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001;38:43–7.
Whibley C, Pharoah PD, et al. p53 polymorphisms: cancer implications. Nat Rev Cancer. 2009;9(2):95–107.
Lakin ND, Jackson SP. Regulation of p53 in response to DNA damage. Oncogene. 1999;18(53):7644–55.
Harper JW, Adami GR, et al. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993;75(4):805–16.
Olivier M, Hollstein M, et al. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008.
Olivier M, Eeles R, et al. The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002;19(6):607–14.
Bougeard G, Brugieres L, et al. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene. 2003;22(6):840–6.
Attwooll CL, McGown G, et al. Identification of a rare polymorphism in the human TP53 promoter. Cancer Genet Cytogenet. 2002;135(2):165–72.
Malkin D. Li-Fraumeni syndrome. Genes Cancer. 2011;2(4):475–84.
Takagi M, Absalon MJ, et al. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell. 2005;123(1):49–63.
Bond GL, Hirshfield KM, et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 2006;66(10):5104–10.
Bougeard G, Baert-Desurmont S, et al. 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.
Tabori U, Nanda S, et al. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. 2007;67(4):1415–8.
Bougeard G, Limacher JM, et al. 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. 2001;38(4):253–7.
Evans DG, Wu CL, et al. BRCA2: a cause of Li-Fraumeni-like syndrome. J Med Genet. 2008;45(1):62–3.
Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68(4):820–3.
Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003;21(3):313–20.
Berger AH, Pandolfi PP. Haplo-insufficiency: a driving force in cancer. J Pathol. 2011;223(2):137–46.
Oren M, Rotter V. Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol. 2010;2(2):a001107.
Li FP, Garber JE, et al. Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. J Natl Cancer Inst. 1992;84(15):1156–60.
Bougeard G, Sesboue R, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet. 2008;45(8):535–8.
Ginsburg OM, Akbari MR, et al. The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer. 2009;8(4):563–7.
Thull DL, Vogel VG. Recognition and management of hereditary breast cancer syndromes. Oncologist. 2004;9(1):13–24.
Eng C, Hampel H, et al. Genetic testing for cancer predisposition. Annu Rev Med. 2001;52:371–400.
Kressner U, Inganas M, et al. Prognostic value of p53 genetic changes in colorectal cancer. J Clin Oncol. 1999;17(2):593–9.
Lammens CR, Aaronson NK, et al. Genetic testing in Li-Fraumeni syndrome: uptake and psychosocial consequences. J Clin Oncol. 2010;28(18):3008–14.
Simpson JL, Carson SA, et al. Preimplantation genetic diagnosis (PGD) for heritable neoplasia. J Natl Cancer Inst Monogr. 2005;34:87–90.
Nichols KE, Malkin D, et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev. 2001;10(2):83–7.
Hisada M, Garber JE, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998;90(8):606–11.
DiGiammarino EL, Lee AS, et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol. 2002;9(1):12–6.
Ribeiro RC, Sandrini F, et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A. 2001;98(16):9330–5.
Pinto EM, Ribeiro RC, et al. TP53-associated pediatric malignancies. Genes Cancer. 2011;2(4):485–90.
Varley JM, McGown G, et al. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65(4):995–1006.
Shlien A, Baskin B, et al. A common molecular mechanism underlies two phenotypically distinct 17p13.1 microdeletion syndromes. Am J Hum Genet. 2010;87(5):631–42.
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Ganguly, A., Chen, Z. (2016). Li-Fraumeni Syndrome. In: Leonard, D. (eds) Molecular Pathology in Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-19674-9_28
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DOI: https://doi.org/10.1007/978-3-319-19674-9_28
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