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Li-Fraumeni Syndrome

Background
Who should be tested
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Li Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous cancer syndrome associated with a wide spectrum of tumours occurring in children and young adults. LFS is caused by mutations in the TP53 gene which has been localized to chromosome 17p13.1. Germline mutations in the TP53 gene predispose individuals to various tumours associated with LFS including early onset sarcomas and breast cancer, osteosarcomas, brain cancer, leukemia and adrenal cortical carcinoma. Other cancers that have been seen in LFS families include lymphoma, melanoma, and cancers of the lung, stomach, ovary, colon/rectum, endometrium, thyroid, pancreas, prostate, and cervix. For individuals with an identified TP53 mutation the risk of developing any invasive cancer is approximately 50% by age 30 and almost 90% by age 70.

LFS is diagnosed in individuals who meet the established clinical criteria and/or are found to carry a TP53 mutation. The “classic” clinical criteria used to diagnose LFS includes: one patient with sarcoma diagnosed under the age of 45, a first-degree relative under the age of 45 with cancer (type not specified) and a third affected first or second-degree relative with either sarcoma at any age or cancer (type not specified) under the age of 45.

Individuals who do not meet the classic criteria may meet one of the following, less stringent criteria. The modified inclusion criteria for Li-Fraumeni-like syndrome (Birch’s criteria) is a proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age, a first or second-degree relative with a typical LFS cancer at any age, and a first- or second-degree relative with any cancer under the age of 60 years.

Incomplete LFS criteria (Chompret’s criteria) includes a child with adrenocortical carcinoma or choroid plexus carcinoma AND a 1st—or 2nd-degree relative with early onset cancer of any kind OR child with rhabdomyosarcoma diagnosed < 3 years of age OR child with osteosarcoma diagnosed < 10 years of age OR proband with early onset multiple synchronous or metachronous cancers, at least one of which is a typical LFS tumor OR patient with early-onset breast cancer (< 45 years) with at least 1 1st- or 2 2nd-degree relatives with cancer diagnosed under age 45 OR any family with numerous cancers in the same parental lineage that have a broad spectrum of cell type lineage (i.e. carcinomas, sarcomas, leukemias, neural crest tumors).

Germline mutations in the TP53 gene have been identified in 80% of families meeting the classic LFS clinical criteria and approximately 95% can be detected by sequencing analysis. Genetic testing can be used to identify relatives at high risk for developing cancer and allow for increased surveillance for LFS-related cancers in those identified to carry a mutation. An individual is at high risk for developing an invasive LFS-related cancer when s/he has inherited one copy of the altered TP53 gene.

Who should be tested

• individuals meeting one of the LFS clinical criteria
• relatives of probands with identified mutations in the TP53 gene
• pregnancies at risk due to a family history of LFS with an identified TP53 family mutation

Testing Methodology

Direct Mutation Analysis: All samples are analyzed by direct sequence analysis of the exons and the intron/exon boundaries of the TP53 gene.

Test Sensitivity: Germline mutations detected by sequencing analysis of the coding exons and the intron/exon boundaries of the TP53 gene have been identified in 80% of families meeting LFS diagnostic criteria.

Gene Dosage Analysis: Samples may also be tested by Multiple Ligation-dependant Probe Amplification (MLPA) methods to detect deletions of the TP53 gene.

Potential Outcomes & Interpretation of Test Results

Cautions:

• Current molecular testing will not detect all possible mutations causing Li Fraumeni syndrome. A negative result does not rule out the possibility that the individual has an unidentified mutation in the TP53 gene, or a mutation in another cancer-susceptibility gene.
• Test results should be interpreted in the context of clinical findings, family history and other laboratory data.
• This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information:

• Online Mendelian Inheritance in Man - Item #151623
• GeneReviews online clinical information resource
  • Funded by the U.S. National Institutes of Health, Developed at the University of Washington, Seattle.
• Understanding Gene Testing
• Lindor NM (1998). Special Article: The Concise Handbook of Family Cancer Symptoms. Jurnal of the National Cancer Institute, Vol 90, No 14.