Heritable TP53-related cancer syndrome/Li Fraumeni syndrome

Heritable TP53-related cancer syndrome (hTP53rc syndrome)/Li Fraumeni syndrome (LFS)

What is hTP53rc syndrome?

The diversity of clinical presentations associated with germline TP53 alterations justifies the expansion of the Li-Fraumeni syndrome (LFS) concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome. hTP53rc syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. A birth prevalence of 1 in 5,000 has been estimated. The diagnosis should be considered in four different clinical situations:

Patient with a tumour suggestive of the syndrome, prior to age 46 years (soft-tissue tumour (sarcoma), bone tumour, a tumour in the outer layer of the adrenal glands (adrenocortical carcinoma), brain tumour, female breast cancer)
AND
at least one first- or second-degree relative with a heritable TP53-related cancer syndrome/Li Fraumeni syndrome tumour before the age of 56 years or with multiple tumours;
Patient with two tumours belonging to the heritable TP53-related cancer syndrome/Li Fraumeni syndrome spectrum, the first being developed before 46 years or patient with a second tumour developed in a field irradiated during the treatment of a first tumour;
Patient with a very rare tumour such as an adrenocortical tumour, a rare brain tumour called choroid plexus tumour, or a specific type of sarcoma called embryonal anaplastic rhabdomyosarcoma;
Female patient with breast cancer before 31 years.

What causes hTP53rc syndrome?

hTP53rc syndrome results from the alteration of one the two parental copies of the TP53 gene encoding the p53 protein. This protein normally acts as a guardian of the genome when DNA damages occur. In patients with an alteration of the gene, the quantity of the normal protein is insufficient, and when DNA damages occur in a cell, they are not corrected and their accumulation leads to the cancerous transformation of the cell.

How is hTP53rc syndrome inherited?

hTP53rc syndrome is a so-called autosomal dominant syndrome: if you inherit the altered copy from only one parent, you can get the disease. In most of the families, the mutation is inherited from the mother or the father, but new alterations occurring in sperm or eggs can end up in every cell of the child and represent at least 14% of the cases.

The risk for a mutation carrier to develop cancer is quite diverse, even within the same family, indicating that some adult mutation carriers do not develop cancer. The risk depends on the type of the mutation and probably on the presence of other genetic variations which act as modifier factors.

Radiotherapy and genotoxic chemotherapies contribute to the development of secondary tumours. Therefore radiotherapy should be avoided and surgical treatment prioritized, but only if this is possible and does not compromise the treatment of cancer.

What are the surveillance options for hTP53rc syndrome?

According to the Guidelines for the Li-Fraumeni and Heritable TP53-related cancer syndromes - Guidelines for the identification of individuals who should be tested for germline disease-causing TP53 variants and for their subsequent clinical management written by ERN GENTURIS:

The surveillance protocols are based, from the first year of life, on abdominal ultrasound every 6 months, annual whole body MRI, annual brain MRI, and in women from 20 years on annual breast MRI. The benefits of such heavy protocols should be carefully analysed and discussed in each family.

Clinical practice guideline

Written by ERN GENTURIS

Heritable TP53-related cancer syndrome/Li Fraumeni syndrome guideline - Guidelines for the Li-Fraumeni and Heritable TP53-related cancer syndromes

ERN GENTURIS healthcare providers

A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.

Patient associations for hereditary cancer syndromes

A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.