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, the videocast of the Li-Fraumeni Syndrome Workshop 2010. and the following publications:

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.

Germline TP53 Mutations and the Changing Landscape of Li-Fraumeni Syndrome. Kamihara J1, Rana HQ, Garber JE. Hum Mutat. 2014 Jun;35(6):654-62.

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.

Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, Malkin D. Lancet Oncol. 2011 Jun;12(6):559-67. Epub 2011 May 19


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.


Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Nichols KE, Malkin D, Garber JE, Fraumeni JF Jr, Li FP. Cancer Epidemiol Biomarkers Prev. 2001 Feb;10(2):83-7.


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.


Other interesting papers:

The breast cancer immunophenotype of TP53-p.R337H carriers is different from that observed among other pathogenic TP53 mutation carriers. Fitarelli-Kiehl M, Giacomazzi J, Santos-Silva P, Graudenz MS, Palmero EI, Michelli RA, Achatz MI, de Toledo Osório CA, de Faria Ferraz VE, Picanço CG, Ashton-Prolla P. Fam.Cancer. 2015 Jun;14(2):333-6.

Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. Zerdoumi Y, Aury-Landas J, Bonaïti-Pellié C, Derambure C, Sesboüé R, Renaux-Petel M, Frebourg T, Bougeard G, Flaman JM. Hum Mutat. 2013 Mar;34(3):453-61.

Increased oxidative metabolism in the Li-Fraumeni syndrome. Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU, Strong LC, Talagala SL, Balaban RS, Kang JG, Hwang PM. N Engl J Med. 2013 Mar 14;368(11):1027-32.

Increased oxidative damage in carriers of the germline TP53 p.R337H mutation. Macedo GS, Lisbôa da Motta L, Giacomazzi J, Netto CB, Manfredini V, Vanzin CS, Vargas CR, Hainaut P, Klamt F, Ashton-Prolla P. PLoS One. 2012 7(10):e47010.

Routine TP53 testing for breast cancer under age 30: ready for prime time? McCuaig JM, Armel SR, Novokmet A, Ginsburg OM, Demsky R, Narod SA, Malkin D.Fam Cancer. 2012 Aug 1.

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.


Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Shlien A, Tabori U, Marshall CR, Pienkowska M, Feuk L, Novokmet A, Nanda S, Druker H, Scherer SW, Malkin D. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11264-9.


Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Tabori U, Nanda S, Druker H, Lees J, Malkin D. Cancer Res. 2007 Feb 15;67(4):1415-8.


The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Achatz MI, Olivier M, Calvez FL, Martel-Planche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Rocha JC, Vettore AL, Hainaut P. Cancer Letters 2007 Jan 8;245(1-2):96-102.


MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ. Cancer Res. 2006 May 15;66(10):5104-10.


BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Lalloo F, Varley J, Moran A, Ellis D, O'dair L, Pharoah P, Antoniou A, Hartley R, Shenton A, Seal S, Bulman B, Howell A, Evans DG. Eur J Cancer. 2006 May;42(8):1143-50.


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.


Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Wong P, Verselis SJ, Garber JE, Schneider K, DiGianni L, Stockwell DH, Li FP, Syngal S. Gastroenterology. 2006 Jan;130(1):73-9.


Genetic mapping of a third Li-Fraumeni syndrome predisposition locus to human chromosome 1q23. Bachinski LL, Olufemi SE, Zhou X, Wu CC, Yip L, Shete S, Lozano G, Amos CI, Strong LC, Krahe R. Cancer Res. 2005 May;42(8):1143-50.


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.