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Li-Fraumeni syndrome
2000-12-01
Jenny M Varley
Affiliation
Cancer Genetics Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 9BX, UK
Identity
Name
Li-Fraumeni syndrome
Note
families with Li-Fraumeni syndrome (LFS) are defined by: a proband with a sarcoma aged under 45 years, with a first degree relative with cancer under 45 years and another first or second degree relative with any cancer under 45 years or a sarcoma at any age
Inheritance
autosomal dominant, high penetrance (100% lifetime risk in females, 75% in males)
Omim
151623 , 609265 , 609266
Mesh
D016864
Orphanet
524 Li-Fraumeni syndrome
Umls
C0085390
Clinics
Phenotype and clinics
no associated dysmorphologies or abnormalities
Neoplastic risk
very high
the main neoplastic risks are bone, cartilage and soft tissue sarcomas, early-onset female breast cancer, brain and spinal cord tumours, childhood adrenocortical tumours, Wilms tumour and malignant phyllodes tumours
there is no increased incidence of a number of cancers which occur frequently within the population, such as colorectal, lung, bladder and gynaecological malignancies
some other tumour types occur rarely, but more frequently than expected; these include pancreas, peripheral nervous system, leukaemia and stomach
Genes involved and Proteins
Description
11 exons, the first of which is non-coding
Function
p53 is the most commonly mutated gene in human cancers possessing multiple properties; p53 has two major roles
firstly in cell cycle arrest, predominantly in the G1 phase of the cell cycle, but also with a role in G2 and mitotic checkpoints
secondly the induction of apoptosis (programmed cell death)
both these are induced upon DNA damage, and the response depends on many things including the type of damage and the cell type
p53 is a transcription factor with a central sequence-specific DNA binding domain and a N-terminal transactivation domain; upon DNA damage, the level of p53 increases markedly, and the DNA-binding properties are activated; the levels of p53 are regulated primarily post-transcriptionally (including phosphorylation and acetylation)
Germinal
there are over 200 published reports of germline mutations
over 75% of families with classic LFS have a germline TP53 mutation
lower proportions of families with some features of LFS have such mutations
children with adrenocortical carcinoma have an extremely high incidence of germline mutations (over 80%)the spectrum of mutations in the germline is superficially the same as somatic mutations, but there are some significant differences
Description
14 exons
Function
a protein kinase which is required for DNA damage and replication checkpoints; CHK2 is phosphorylated by
ATM
, and in turn can phosphorylate p53 at serine-20; it appears that germline hCHK2 mutations are uncommon in LFS
Bibliography
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External Links
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OMIM
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MeSH
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