Li-Fraumeni syndrome

Li-Fraumeni syndrome is associated with a high risk for a broad spectrum of cancers, the majority being: adrenocortical carcinoma, breast cancer, central nervous system tumours, osteosarcoma, and soft-tissue sarcoma. Additional tumours include leukaemia, gastrointestinal, lung, prostate, kidney, and skin malignancies. The lifetime risks of cancer for women and men with classic LFS are 90% and 70%, respectively, and 50% of cancers occur prior to age 40 years, with an onset span from childhood to late adulthood. Clinical presentation is highly variable within and between families, reflecting the wide tumour spectrum and onset range. Affected individuals have a high risk of developing a second primary cancer and prior radiation or chemotherapy may further increase the risk of subsequent malignancy.

The estimated prevalence is 1/3,000-1/10,000 (GeneReviews, 2024).

Li-Fraumeni syndrome is caused by germline pathogenic variants in TP53 (17p13.1), identified in approximately 90% of probands meeting LFS criteria. TP53 encodes p53, a tumour-suppressor transcription factor activated by cellular stress that mediates cell-cycle arrest, apoptosis, senescence, DNA repair, and differentiation. Pathogenic variants cause loss of function through impaired DNA binding and reduced transcriptional response to DNA damage; certain variants additionally exert a dominant-negative effect on the wild-type allele.

Li-Fraumeni syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis of Li-Fraumeni syndrome rests on established consensus criteria. The classic Li-Fraumeni criteria () and the modified Chompret criteria are widely applied. Meeting either set of criteria constitutes the clinical diagnosis. The diagnosis is further established by family-history and confirmed by molecular genetic testing.

Main differential diagnoses include:

• BRCA1– and BRCA2-associated : predominantly adult-onset breast, ovarian, pancreatic, prostate, and melanoma cancers without childhood-onset tumours; BRCA1, BRCA2
• Constitutional mismatch repair deficiency (CMMRD): childhood-onset gastrointestinal cancer or polyps, malignant brain tumours, haematologic cancers and café au lait macules; autosomal recessive; MLH1, MSH2, MSH6, PMS2
• CHEK2-related cancer susceptibility: predominantly adult-onset breast, and cancers; not associated with adrenocortical carcinoma, or osteosarcoma; CHEK2

• Establishing the diagnosis through identification of the underlying pathogenic variant.
• Enabling specific and individualised surveillance, including whole-body MRI where indicated, as the prerequisite for targeted medical care; decisions on surveillance modalities and intervals rest with the treating physicians in consultation with the affected individual.
• Allowing predictive testing of at-risk family members once the familial pathogenic variant has been identified.

• Schneider K, Zelley K, Nichols KE, Schwartz Levine A, Garber J. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2025 May 1]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301488. Available from:
• 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 National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122(23):3673-3681. doi: 10.1002/cncr.30248. PMID: . PMCID: PMC5115949.
• Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. Journal of Clinical Oncology. 2015;33(21):2345-52. doi: 10.1200/JCO.2014.59.5728. PMID: .
• Amadou A, Achatz MIW, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Current Opinion in Oncology. 2018;30(1):23-29. doi: 10.1097/CCO.0000000000000423. PMID: .