Transcript What is Li-Fraumeni syndrome?

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).
Molecular Genetics of Li-Fraumeni Syndrome
Gene Symbol
Chromosomal
Locus
Protein Name
CHEK2
22q12.1
Serine/threonineprotein 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 DNAdamaging 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 wildtype 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.