Cancer prone diseases
Educational items 🇬🇧 🇪🇸 🇫🇷 🇩🇪 🇮🇹 🇨🇳
To the top
Other actions (beta)
Download as PDF
Jenny M Varley
Cancer Genetics Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 9BX, UK
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
autosomal dominant, high penetrance (100% lifetime risk in females, 75% in males)
151623 , 609265 , 609266
524 Li-Fraumeni syndrome
Phenotype and clinics
no associated dysmorphologies or abnormalities
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
11 exons, the first of which is non-coding
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)
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
a protein kinase which is required for DNA damage and replication checkpoints; CHK2 is phosphorylated by
, and in turn can phosphorylate p53 at serine-20; it appears that germline hCHK2 mutations are uncommon in LFS
Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.
Bell DW et al
Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.
Birch JM et al
Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.
Birch JM et al
P53 germline mutations in childhood cancers and cancer risk for carrier individuals.
Chompret A et al
A cancer family syndrome in twenty-four kindreds.
Li FP et al
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.
Malkin D et al
Li-Fraumeni syndrome--a molecular and clinical review.
Varley JM et al
Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.
Varley JM et al
Please, confirm that you want to generate a PDF file of this page.
This may take some seconds once process has started. Then it will be opened automatically.
Wait a moment, we are generating the document...