Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Li-Fraumeni Syndrome (LFS) [C97]

OMIM numbers: 151623, 191170 (TP53)

Dr. rer. nat. Karin Mayer

Scientific Background

Li-Fraumeni syndrome (LFS) is a rare, familial tumor disease, characterized by multiple tumors (soft-tissue sarcomas, osteosarcomas, brain tumors, breast cancer, leukemia, adrenocortical carcinomas). Inheritance is autosomal dominant. The strict classic criteria for a diagnosis are as follows:

  • index patient with sarcoma prior to age 45 years
  • first-degree relative with carcinoma prior to age 45 years
  • additional first or second-degree relative with a carcinoma prior to age 45 years or sarcoma diagnosed at any age

The criteria can be categorized into four subgroups according to the number and type of tumor in affected relatives (see table). Families with a history of tumors who fulfill the extended but not the classic criteria for Li-Fraumeni syndrome are also called Li-Fraumeni-like (LFS-L).

Li-Fraumeni syndrome is caused by germline mutations in the tumor suppressor gene TP53. Mutations are found in TP53 in up to 70% of all families with classic LFS; however, they are found in only 20% of all patients with Li-Fraumeni-like syndrome. Heterozygous TP53 germline mutations lead in a large number of cases due to mutation of the still intact allele (loss of heterozygosity, LOH) to a total loss of function of the gene product p53. The cellular tumor antigen p53 plays a major role as the “guardian of the genome”, since it can transfer the cell into the G0 phase at the checkpoint between the G1 and S phase of the cell cycle. The cells division stops to repair potential damage in the cellular DNA or to initiate the programmed cell death (apoptosis). Somatic mutations in TP53 are, along with germline mutations in LFS families, the most common genetic change in the case of malignant tumors.

Indications for a TP53 mutation analysis are as follows:

  • index patient with a tumor belonging to the LFS spectrum (soft-tissue sarcoma, osteosarcoma, breast cancer, brain tumor, adrenocortical sarcoma, leukemia, bronchoalveolar lung carcinoma) prior to age 46 years


  • at least one first or second degree relative with a LFS tumor (excluding breast cancer if the index patient is suffering from breast cancer) prior to 56 years of age


  • index patient with multiple tumors (except breast cancer), two of which belong to the LFS spectrum and the manifestation of the first tumor was prior to 46 years of age


  • index patient with sarcoma of the adrenal gland or choroid plexus carcinomas, independently of family history

In few families with Li-Fraumeni or Li-Fraumeni-like syndrome, mutations were detected in the CHEK2 gene. CHEK2 encodes a serine threonine kinase which can phosphorylate p53 and which also plays a crucial role in controlling DNA repair and replication.