What is Li-Fraumeni syndrome? Li-Fraumeni syndrome is a rare inherited disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The cancers associated with Li-Fraumeni syndrome include osteosarcoma (a form of bone cancer), soft tissue sarcoma (cancer that occurs in soft tissues such as muscle), breast cancer, brain tumors, adrenocortical carcinoma (cancer of the adrenal gland, a small hormone-producing gland on top of each kidney), and leukemia (a cancer of blood-forming tissue). Other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.

How common is Li-Fraumeni syndrome? Li-Fraumeni syndrome is rare. Fewer than 400 families worldwide have been diagnosed with the condition.

What genes are related to Li-Fraumeni syndrome? The CHEK2 and TP53 genes are associated with Li-Fraumeni syndrome. More than half of all families with this condition have inherited mutations in the TP53 gene. TP53 is a tumor suppressor gene, which means that it normally helps control the growth and division of cells. Mutations in TP53 can allow cells to divide in an uncontrolled way and form tumors. Other genetic and environmental factors are also likely to affect the risk of cancer in people with TP53 mutations. A few families with cancers characteristic of Li-Fraumeni syndrome do not have TP53 mutations, but have mutations in the CHEK2 gene. Like the TP53 gene, CHEK2 is a tumor suppressor gene. Researchers are uncertain whether CHEK2 mutations actually cause Li-Fraumeni syndrome or are merely associated with an increased risk of certain cancers (including breast cancer).

Gene Symbol Chromosomal Locus Protein Name Molecular Genetics of Li-Fraumeni Syndrome Gene Symbol Chromosomal Locus Protein Name CHEK2 22q12.1 Serine/threonine-protein kinase Chk2 TP53 17p13.1 Cellular tumor antigen p53

How do people inherit Li-Fraumeni syndrome? Li-Fraumeni syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing cancer. In most cases, an affected person has one parent with the condition.

Diagnosis and treatment Li-Fraumeni Syndrome is diagnosed if the following three criteria are met: the patient has been diagnosed with a sarcoma at a young age (below 45), a first-degree relative has been diagnosed with any cancer at a young age (below 45), and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age. Genentic 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. If caught early the cancers can often be successfully treated. Unfortunately, people with Li-Fraumeni are likely to develop another primary malignancy at a future time.

TP53 germline mutations The TP53 gene on chromosome 17p13 has 11 exons that span 20 kb. The Exon 1 is non-coding, and exons 5 to 8 are remarkably conserved among vertebrates. The TP53 gene encodes a 2.8 kb transcript encoding a 393 amino-acid protein, which is widely expressed at low levels. This protein is a multi-functional transcription factor involved in the control of cell cycle progression, of DNA integrity and of the survival of cells exposed to DNA-damaging agents as well as several non-genotoxic stimuli. TP53 mutant proteins differ from each other in the extent to which they have lost suppressor function and in their capacity to inhibit wild-type TP53 in a dominant-negative manner. In addition, some TP53 mutants appear to exert an oncogenic activity of their own, but the molecular basis of this gain-of-function phenotype is still unclear. The functional characteristics of each mutant TP53 protein may depend, at least in part, on the degree of structural perturbation that the mutation imposes on the protein.

TP53 germline mutations. Similar to sporadic cancers, TP53 germline mutations preferentially occur in hotspot regions. Germline mutations prevail in codons 245 and 248. From: H. Ohgaki et al., In: Pathology and Genetics of Tumours of the Nervous System, P. Kleihues and W.K. Cavenee eds., pp. 231-234, IARC Press: Lyon 2000).

Age distribution in relation to tumour type. Age distribution of Li-Fraumeni patients according to tumour type.

Either activating mutations of an oncogene or inactivating mutations of a tumor suppressor gene result in genetic tumor-prone syndromes. There are two modes of inactivation of tumor suppressor genes. Like some of p53 mutations in Li-Fraumeni syndrome, the protein translated from the mutated allele may function as a dominant negative mutant, leading to haploinsufficiency in heterozygous patients. More commonly Knudson's "two-hit" theory applies, e.g., Rb mutations. Cells of heterozygous patients undergo somatic mutation to lose the wild-type allele.