Li-Fraumeni syndrome

2000-12-01   Jenny M Varley  

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

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    106174731999Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.Bell DW et al
    97648161998Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.Birch JM et al
    81188191994Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.Birch JM et al
    108642002000P53 germline mutations in childhood cancers and cancer risk for carrier individuals.Chompret A et al
    34092561988A cancer family syndrome in twenty-four kindreds.Li FP et al
    19787571990Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.Malkin D et al
    92187251997Li-Fraumeni syndrome--a molecular and clinical review.Varley JM et al
    104863181999Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.Varley JM et al