Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome due to pathogenic/likely pathogenic (P/LP) variants in the TP53 gene. Cancers associated with LFS include sarcoma, leukemia, breast, lung, brain and other cancers, especially when these are diagnosed at a young age. In addition, a variety of other neoplasms may occur (Maxwell et al., 2022). LFS is inherited in an autosomal dominant pattern, but up to 20% of TP53 may occur de novo (Schon and Tischkowitz., 2018). LFS is clinically diagnosed in individuals who meet established criteria or in those who have a germline P/LP variant in the TP53 gene, regardless of the family history of cancer. 

Per current NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate (v.3.2025), TP53 gene analysis may be considered when patients meet any of the following criteria:

  • An individual is from a family with a known TP53 P/LP variant.
  • A diagnosis of classic Li-Fraumeni syndrome (LFS), as defined by presence of all of the following criteria:
    • An individual with a sarcoma diagnosed before age 45 years AND
    • A first-degree relative with any cancer before age 45 years AND
    • An additional first- or second-degree relative in the same lineage with any cancer diagnosed before age 45 years or a sarcoma at any age (Li et al., 1988).
  • A patient meeting any of the Chompret criteria, as outlined below:
    • An individual with a tumor belonging to the LFS tumor spectrum (e.g. soft tissue sarcoma, osteosarcoma, CNS tumor, breast cancer, adrenocortical carcinoma), before age 46 years AND at least one first- or second-degree relative with any of the aforementioned cancers (other than breast cancer if the proband has breast cancer) before age 56 years or with multiple primaries at any age
    • An individual with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum with the initial cancer occurring before the age of 46 years
    • An individual with adrenocortical carcinoma, choroid plexus carcinoma, or rhabdomyosarcoma of embryonal anaplastic subtype, at any age, regardless of the family history 
    • An individual with breast cancer before age 31 years.
  • Personal or family history of pediatric hypodiploid acute lymphoblastic leukemia
  • An affected individual with a P/LP TP53 variant identified on tumor-only genomic profiling, germline testing should be considered in the following scenarios: (1) Those meeting one or more of the other LFS testing criteria listed above after re-evaluation of personal/family history; or (2) Those with cancer diagnosed under the age of 30; or (3) Those with a clinical scenario not meeting these criteria but warranting germline evaluation per clinician discretion. 

The AACR Childhood Cancer Predisposition Workshop published recommendations for consideration of genetic testing for LFS for a child with a diagnosis of low-hypodiploid ALL, as results may influence therapeutic decision making and donor choice for allogeneic hematopoietic stem cell transplantation (allo-HSCT) (Porter et al., 2017). Additional cancer types in which affected children may have germline TP53 P/LP variants, often in the absence of obvious family history, include rhabdomyosarcoma with diffuse anaplasia, choroid plexus carcinoma, Sonic Hedgehog (SHH) medulloblastoma, and osteosarcoma (Kratz et al., 2017).

Historically, testing for TP53 has been limited to individuals whose personal and family histories of cancer were striking for LFS-related tumors and met established guidelines for testing. However, given the development of next generation sequencing technology and the increasing availability of multi-gene cancer panels, P/LP variants in TP53 have been detected in more individuals than would have previously met clinical testing criteria. In these patients, personal and family histories of cancer are less striking than in those with classic LFS. Therefore, the phenotypic spectrum of inherited TP53 P/LP variants may be more broad than initially thought, and additional studies are warranted to determine optimal screening and management for patients with TP53 P/LP variants who do not meet historic criteria (Rana et al., 2018). Furthermore, genotype-phenotype data is emerging that has the potential to assist in personalizing medical management (Rana et al., 2019). Finally, emerging data seem to show that a significant proportion of TP53 gene P/LP variants detected on multi-gene cancer panels are actually somatically acquired as a result of clonal hematopoiesis of unknown potential (CHiP) or constitutional mosaicism (Coffee et al., 2020; Mester et al., 2020).

Management of patients with LFS focuses on early detection of associated cancers including increased breast, dermatologic, and colon cancer screening. Cancer screening recommendations include a combination of physical exams, blood tests, and imaging, which may include full body MRI (Kratz et al., 2017; Villani et al., 2016; Schon and Tischkowitz, 2018; Hanson et al.,2020). Individuals with LFS may consider prophylactic mastectomy given the associated breast cancer risk. Additionally, specific management for LFS-related breast cancer includes mastectomy rather than lumpectomy and avoidance of radiation therapy. Screening for neuroblastoma is recommended specifically for individuals with the TP53 R337H germline variant (Kamihara et al., 2017).

 

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. v.3.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed [March 13, 2025]. To view the most recent and complete version of the guideline, go online to NCCN.org.

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