Li-Fraumeni syndrome

Inherited TP53 mutations are associated with a rare autosomal dominant disorder, the Li-Fraumeni syndrome (LFS). LFS is characterized by multiple primary neoplasms in children and young adults, with a predominance of soft-tissue sarcomas, osteosarcomas, breast cancers, brain tumors and adrenocortical carcinomas.

Several clinical definitions of LFS have been proposed.

The classic Li-Fraumeni syndrome (LFS) (Li et al., 1988) is defined by presence of all of the following criteria:
A proband with a sarcoma diagnosed before age 45 years;
A first-degree relative with any cancer before age 45 years;
A first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age [Li et al 1988].


The Chompret criteria (updated in 2015)(Bougeard et al., 2015) should be used to identify potential TP53 mutation carriers:
Familial presentation:
Proband with tumor belonging to LFS tumor spectrum (eg, premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, CNS tumor, adrenocortical carcinoma) before age 46 years, AND at least one first or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors;
Multiple primary tumors:
Proband with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum and first of which occurred before age 46 years;
Rare tumors:
Patient with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history;
Early-onset breast cancer:
Breast cancer before age 31 yr.


Data on Li-Fraumeni associated TP53 mutations can be searched here.


To learn more on LFS and TP53 germline mutations, see GeneReviews and the videocast of the Li-Fraumeni Syndrome Workshop 2010.


Publications of interest:

Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging, A Meta-analysis. Ballinger ML, Best A, Mai PL, Khincha PP, Loud JT, Peters JA, Achatz MI, Chojniak R, Balieiro da Costa A, Santiago KM, Garber J, O'Neill AF, Eeles RA, Evans DG, Bleiker E, Sonke GS, Ruijs M, Loo C, Schiffman J, Naumer A, Kohlmann W, Strong LC, Bojadzieva J, Malkin D, Rednam SP, Stoffel EM, Koeppe E, Weitzel JN, Slavin TP, Nehoray B, Robson M, Walsh M, Manelli L, Villani A, Thomas DM, Savage SA. 2017 Dec 1;3(12):1634-1639.


Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Kratz CP, Achatz MI, Brugières L, Frebourg T, Garber JE, Greer MC, Hansford JR, Janeway KA, Kohlmann WK, McGee R, Mullighan CG, Onel K, Pajtler KW, Pfister SM, Savage SA, Schiffman JD, Schneider KA, Strong LC, Evans DGR, Wasserman JD, Villani A, Malkin D. 2016 Jun 1;23(11):e38-e45.


Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, Bremer RC, Rosenberg PS, Savage SA. 2016 Dec 1;122(23):3673-3681.


Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaiti-Pellie C, Tinat J, Baert-Desurmont S, Frebourg T. J Clin Oncol. 2015 Jul 20;33(21):2345-52.


Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, Gruber SB, Ford JM, Euhus D, Lebensohn A, Telli M, Pochebit SM, Lypas G, Garber JE. Breast Cancer Res Treat. 2012 Jun;133(3):1125-30.


Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Cancer 2012 Mar 1;118(5):1387-96.


Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L, Chompret A, Bressac-de Paillerets B, Stoppa-Lyonnet D, Bonaiti-Pellie C, Frebourg T. J Med Genet. 2006 Jun;43(6):531-3.


Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, Han JH, Lowstuter K, Longmate J, Sommer SS, Weitzel JN. J Clin Oncol. 2009 Mar 10;27(8):1250-6.


A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ. Cell 2004 Nov 24;119(5):591-602.


Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA. Cancer Res. 2003 Oct 15;63(20):6643-50.


Germline TP53 mutations and Li-Fraumeni syndrome. Varley JM. Hum Mutat 2003 Mar;21(3):313-20.


Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, Eden OB, Varley JM. Oncogene 2001 Aug 2;20(34):4621-8.


Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Birch JM, Blair V, Kelsey AM, Evans DG, Harris M, Tricker KJ, Varley JM. Oncogene. 1998 Sep 3;17(9):1061-8.


Li-Fraumeni syndrome--a molecular and clinical review. Varley JM, Evans DG, Birch JM. Br J Cancer. 1997;76(1):1-14.