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Li-Fraumeni syndrome

Identity

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)

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

     
    Gene NameTP53
    Location 17p13
    DNA/RNA
    Description 11 exons, the first of which is non-coding
    Protein
    Description p53, a 393 amino acid protein
    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)
  • Mutations
    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

  •  
    Gene NamehCHK2
    Location 22q12.1
    DNA/RNA
    Description 14 exons
    Protein
    Description a 543 amino acid protein with homology to Saccharomyces cerevisiae RAD53 and Schizosaccharomyces pombe cds1.
    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

    External links

    OMIM151623
    OrphanetLi-Fraumeni syndrome

    Bibliography

    Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?
    Li FP, Fraumeni JF Jr
    Annals of internal medicine. 1969 ; 71 (4) : 747-752.
    PMID 5360287
     
    A cancer family syndrome in twenty-four kindreds.
    Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW
    Cancer research. 1988 ; 48 (18) : 5358-5362.
    PMID 3409256
     
    Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.
    Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA
    Science (New York, N.Y.). 1990 ; 250 (4985) : 1233-1238.
    PMID 1978757
     
    Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.
    Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Jones PH, Binchy A, Crowther D
    Cancer research. 1994 ; 54 (5) : 1298-1304.
    PMID 8118819
     
    Li-Fraumeni syndrome--a molecular and clinical review.
    Varley JM, Evans DG, Birch JM
    British journal of cancer. 1997 ; 76 (1) : 1-14.
    PMID 9218725
     
    Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.
    Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ, Evans DG, Birch JM
    Cancer research. 1997 ; 57 (15) : 3245-3252.
    PMID 9242456
     
    Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.
    Birch JM, Blair V, Kelsey AM, Evans DG, Harris M, Tricker KJ, Varley JM
    Oncogene. 1998 ; 17 (9) : 1061-1068.
    PMID 9764816
     
    Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.
    Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA
    Science (New York, N.Y.). 1999 ; 286 (5449) : 2528-2531.
    PMID 10617473
     
    Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.
    Varley JM, McGown G, Thorncroft M, James LA, Margison GP, Forster G, Evans DG, Harris M, Kelsey AM, Birch JM
    American journal of human genetics. 1999 ; 65 (4) : 995-1006.
    PMID 10486318
     
    P53 germline mutations in childhood cancers and cancer risk for carrier individuals.
    Chompret A, Brugiˆ®res L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, Frˆ©bourg T, Lemerle J, BonaˆØti-Pelliˆ© C, Feunteun J
    British journal of cancer. 2000 ; 82 (12) : 1932-1937.
    PMID 10864200
     
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

    Contributor(s)

    Written12-2000Jenny M Varley
    Cancer Genetics Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 9BX, UK

    Citation

    This paper should be referenced as such :
    Varley, JM
    Li-Fraumeni syndrome
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):76-77.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Kprones/LiFraumeniID10011.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Wed Jul 30 15:02:13 CEST 2014


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