Li-Fraumeni syndrome

Identity

Atlas_Id	10011
Genes implicated in	CDKN2A  CHEK2  PTEN  TP53
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 Name	TP53
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 Name	CHEK2
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

Bibliography

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

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

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

P53 germline mutations in childhood cancers and cancer risk for carrier individuals.

Chompret A, Brugières L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon MG, Bressac-de Paillerets B, Frébourg T, Lemerle J, Bonaïti-Pellié C, Feunteun J

British journal of cancer. 2000 ; 82 (12) : 1932-1937.

PMID 10864200

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

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

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

Citation

This paper should be referenced as such :

Varley, JM

Li-Fraumeni syndrome

Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):76-77.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/LiFraumeniID10011.html

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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