Li–Fraumeni syndrome

Li–Fraumeni syndrome
Classification and external resources
ICD-9-CM 758.3
OMIM 151623
DiseasesDB 7450
eMedicine ped/1305
MeSH D016864

Li–Fraumeni syndrome is a rare cancer predisposition hereditary disorder characterized as autosomal dominant. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients.[1] This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.

The syndrome is linked to germline mutations of the p53 tumor suppressor gene,[2] which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The mutations can be inherited, or can arise from de novo mutations early in embryogenesis, or in one of the parent's germ cells.


Li–Fraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout one's life.[3]


Li–Fraumeni syndrome (LFS) is relatively rare; as of 2011, cases had been reported in more than 500 families.[4] The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified four families in which siblings or cousins of rhabdomyosarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome.[5][6] Identification of TP53 as the gene affected by mutation was suggested by the same approach. Over half of the cancers in Li-Fraumeni families had been previously associated with inactivating mutations of the p53 gene, and, in one primary research study, DNA sequencing in samples taken from five Li–Fraumeni syndrome families showed autosomal dominant inheritance of a mutated TP53 gene.[5][6]


LFS1: Mutations in TP53

LFS2: Mutations in CHEK2

Another variant of Li–Fraumeni that remains somewhat controversial, is a mutation of the CHEK2 (or CHK2) gene.[4] CHK2 is also a tumor suppressor gene. CHK2 regulates the action of p53. CHK2 is activated by ATM which detects DNA damage, and in this way DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death).


Families that do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-like".[4] LFS-like individuals generally do not have any detectable p53 mutations, and tend to be diagnosed on either the Birch or Eeles criteria.

A third locus has been mapped to the long arm of chromosome 1 (1q23) but no gene has yet been identified.


The classical LFS malignancies - sarcoma, cancers of the breast, brain and adrenal glands - comprise about 80% of all cancers that occur in this syndrome.

The risk of developing any invasive cancer (excluding skin cancer) is ~50% by age 30 (1% in the general population) and is 90% by age 70. Early onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft tissue sarcomas (20%), bone sarcoma (15%) and brain tumors - especially glioblastomas - (13%). Other tumours seen in this syndrome include leukaemia, lymphoma and adrenocortical carcinoma.

~90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males as well as increased estrogen levels in females.

The risks of sarcoma, female breast cancer and haematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population.

Other tumours reported in this syndrome but not yet proved to be linked with it include melanoma, Wilm's and other kidney tumors, hepatacellular carcinoma, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal and prostate cancers.

80% of children with adrenocortical carcinoma and 2%-10% of childhood brain tumors have p53 mutations.

2%-3% of osteosarcomas, 9% rhabdomyosarcomas and 7%-20% patients with multiple primary tumors have p53 mutations.

Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life.[9]


Li–Fraumeni syndrome is diagnosed if the following three criteria are met:

Other criteria have also been proposed, such as the Birch criteria,[10] which require:

In addition, there has been suggestion of an Eeles criterion:[11]


Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).

Chompret criteria

A 2009 revision of the traditional Chompret criteria for screening has been proposed:[12]

A proband who has:

and at least one of the following:


Recommendations for individuals from families affected by the syndrome include:


Prophylactic mastectomy to reduce the risk of breast cancer is an option.

See also


  1. Li F.P.; Fraumeni J.F. (October 1969). "Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?". Ann. Intern. Med. 71 (4): 747–52. doi:10.7326/0003-4819-71-4-747. PMID 5360287.
  2. Varley J.M. (March 2003). "Germline TP53 mutations and Li-Fraumeni syndrome". Hum. Mutat. 21 (3): 313–20. doi:10.1002/humu.10185. PMID 12619118.
  3. Hisada, M.; Garber, J. E.; Li, F. P.; Fung, C. Y.; Fraumeni, J. F. (1998). "Multiple Primary Cancers in Families With Li-Fraumeni Syndrome". JNCI Journal of the National Cancer Institute. 90 (8): 606–611. doi:10.1093/jnci/90.8.606. ISSN 0027-8874.
  4. 1 2 3 4 5 6 Malkin, D. (2011). "Li-Fraumeni Syndrome". In Levine, Arnold J. Genes and Cancer (PDF). 2. pp. 475–484. doi:10.1177/1947601911413466. PMC 3135649Freely accessible. Retrieved 22 February 2016.
  5. 1 2 Malkin, D.; Li, F.P.; Strong, L.C.; Fraumeni Jr, J.F.; Nelson, C.E.; Kim, D.H.; Kassel, J.; Gryka, M.A.; Bischoff, F.Z. Tainsky, M.A. et al. (1990). "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms". Science. 250 (4985, 30 November): 1233–1238. doi:10.1126/science.1978757. PMID 1978757.
  6. 1 2 Malkin D. & Friend, S.H. (1993). "Correction: a Li-Fraumeni syndrome p53 mutation. Erratum for "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms"". Science. 259 (5097, 12 February): 878. PMID 8438145.
  7. Chène, P. (2001). "The Role of Tetramerization in p53 function" (online, print review). Oncogene. 20 (21): 2611–2617. doi:10.1038/sj.onc.1204373.
  8. Willis, Amy; Jung, Eun Joo; Wakefield, Therese & Chen, Xinbin (2004). "Mutant p53 Exerts a Dominant Negative Effect by Preventing Wild-Type p53 from Binding to the Promoter of its Target Genes". Oncogene. 23: 2330–2338. doi:10.1038/sj.onc.1207396. Retrieved 22 February 2016.
  9. Cho Y, Kim J, Kim Y, Jeong J, Lee KA (2013) A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer. Ann Lab Me 33(3):212-216. doi: 10.3343/alm.2013.33.3.212.
  10. Birch JM, Hartley AL, Tricker K, Prosser J, Condie A, Kelsey A, Harries M, Jones P, Binchy A, Crowther D, Craft A, Eden O, Evans D, Thompson E, Mann J, Martin J, Mitchell E, Santibanez-Koref M (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54:1298–304.
  11. Eeles, R. (1995). "Germline mutations in the TP53 gene". Cancer Surveys. 25: 101–124. ISSN 0261-2429. PMID 8718514.
  12. Tinat J.; Bougeard G.; Baert-Desurmont, S.; Vasseur, S.; Martin, C.; Bouvignies, E.; Caron, O.; Bressac-de Paillerets, B.; Berthet, P.; Dugast, C.; Bonaiti-Pellie, C. & Stoppa-Lyonnet, D. (2009). "2009 Version of the Chompret criteria for Li Fraumeni syndrome" (research correspondence). J. Clin. Oncol. 27: 1–2. Retrieved 22 February 2016.
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