What Is Li-Fraumeni Syndrome?

Unfortunately, cancer is a common illness. According to Cancer Research UK, 1 in 2 of us will develop cancer in our lifetime and this risk generally increases with age.¹ However, some people have a much higher risk of cancer than others due to changes in their DNA.

Li-Fraumeni syndrome is a rare genetic cancer syndrome. Affected families often have several members who develop cancer at younger ages than one would typically expect, and who may develop several primary cancers during their life.² 

Read on to find out more about Li-Fraumeni syndrome and issues that it can present for affected families. 

Overview

Li-Fraumeni syndrome is a genetic cancer syndrome caused by a change, also known as a mutation, in the TP53 gene.² TP53 is a tumour-suppressor gene.³

Cancer arises when changes in our DNA within a cell go unchecked. These changes allow the cell to grow and divide in an uncontrolled way to form more cancer cells that interfere with normal bodily tissue and cause problems for our health.⁴ TP53 reduces our risk of cancer by preventing uncontrolled cell growth.³

TP53 doesn’t work properly in people with Li-Fraumeni syndrome because the gene contains a mutation. This places these people with the gene mutation at increased risk of cancer, especially the following:²

• Breast cancer
• Osteosarcoma
• Soft tissue sarcoma
• Adrenocortical tumours
• Central nervous system (CNS) tumours

At least 70% of people assigned male at birth (AMAB) and at least 90% of people assigned female at birth (AFAB) with Li-Fraumeni syndrome will develop cancer during their lifetime.² 

The management of Li-Fraumeni syndrome involves three components:²

• Risk reduction measures
• Cancer surveillance measures
• Treatment for active cancer

Causes of Li-Fraumeni Syndrome

We now know that Li-Fraumeni syndrome is caused by a mistake in the TP53 gene². 

A gene is a section of DNA, much like a recipe, that tells our cells how to make a particular protein. A protein is a molecule that does a special job within our cells.⁵ TP53 tells our cells how to make a protein called p53. When DNA within a cell is damaged, p53 acts to either repair the damage or kill the offending cell, thus preventing the formation of a cancer.³ 

There are two copies of every gene inside each of our cells. A person only needs to have a mutation in one of their two copies of the TP53 gene in order to develop Li-Fraumeni syndrome.² This makes Li-Fraumeni syndrome an autosomal dominant disorder. Other autosomal dominant conditions include tubular sclerosis and Marfan syndrome.⁶ 

When a person with Li-Fraumeni syndrome has a child, they will pass one of their two copies of the TP53 gene to that child. There is a half (50%) chance that they will pass their normal copy, and a half (50%) chance that they will pass the copy that contains the spelling mistake. So, we can say that any child of a person with Li-Fraumeni syndrome is at 50% risk of inheriting the condition, as one copy is sufficient to cause the syndrome.² The child’s second copy of the TP53 gene will come from their other parent. 

Occasionally, Li-Fraumeni syndrome occurs in a person with two unaffected parents. This means that the mutation in their TP53 gene has occurred for the first time in them. This type of new mutation is called a de novo mutation.²

Signs and Symptoms of Li-Fraumeni Syndrome

We know that Li-Fraumeni syndrome places a person at increased risk of a number of cancers. The signs and symptoms a person presents with will vary depending on which cancer they have developed. You can click on the hyperlinks below to learn more about the signs and symptoms of each cancer. 

• Breast cancer: This is the most common cancer amongst people AFAB with Li-Fraumeni syndrome, presenting at a median age of 33 years old.²
• Osteosarcoma: Osteosarcoma is a type of bone cancer. In those with Li-Fraumeni syndrome, it occurs at a median age of 14 years old.²
• Soft tissue sarcoma: This cancer affects various soft tissues of the body such as muscle and fat. Soft tissue sarcomas are the most common cancers affecting children with Li-Fraumeni syndrome.²
• Adrenocortical tumours: These tumours affect the adrenal glands and most often occur in children with Li-Fraumeni syndrome. 
• CNS tumours: Cancers of the central nervous system affect the brain and spinal cord. The median age of diagnosis amongst those with Li-Fraumeni syndrome is 16 years old.

Other cancers that occur more commonly amongst those with Li-Fraumeni syndrome include leukaemia, lymphoma and gastrointestinal tumours. 

Diagnosis

A diagnosis of Li-Fraumeni syndrome can be made clinically or via genetic testing.²

A clinical diagnosis can be made if a person fulfils all three of the following criteria:⁷

• The person is diagnosed with sarcoma before the age of 45.
• The person has a first-degree relative (a parent, sibling or child) diagnosed with cancer at any age.
• The person has a first or second-degree (half-sibling, sibling of a parent, grandparent, grandchild or child of a sibling) diagnosed with any cancer before the age of 45 or with sarcoma at any age.

Genetic testing is offered to those who are suspected of having Li-Fraumeni syndrome. It is also offered to people who are known to have an affected relative and so are at risk themselves. Genetic counselling should be offered to those who are offered a genetic test. A genetic counsellor shares information about the condition and diagnostic process, helping a person to understand the various implications of either a positive or negative result. This helps them to make an informed decision about whether they wish to proceed with the test.²

Management and treatment of Li-Fraumeni syndrome

Risk reduction

Those with Li-Fraumeni syndrome can reduce their risk of cancer by avoiding carcinogens such as tobacco, ionising radiation, UV radiation and alcohol. Some people may choose to undergo a prophylactic (preventative) double mastectomy (to remove both breasts) to reduce their risk of breast cancer.²

Surveillance

Those with Li-Fraumeni syndrome may choose to undergo regular examinations, scans and tests to check for the development of cancer(s). Comprehensive surveillance consists of:²

• Physical examinations 

• Complete examination every 3-4 months until the age of 18 and then every six months. 
• Annual neurological examination.
• Annual dermatological examinations from the age of 18.
• Breast examination every 6-12 months for people AFAB from the age of 20-25. 

• Scans

• Annual magnetic resonance imaging (MRI) scans of the whole body and brain.
• Ultrasound scans of the abdomen and pelvis every 3-4 months until the age of 18 and then annually.
• Annual breast MRI for people AFAB from the age of 20-30.
• Annual breast MRI and mammogram for people AFAB between age 30-75. 

• Other tests

• Colonoscopy and endoscopy every 2-5 years from the age of 25. 

Treatment of active cancer

If a person with Li-Fraumeni syndrome is diagnosed with cancer, they will be offered treatment. The type of treatment will depend on a number of factors including cancer type, stage and the overall health of the person. Treatment options may include surgery, chemotherapy, and supportive or palliative care. Radiation therapy is best avoided if possible because radiation therapy increases the risk of additional cancers in those with Li-Fraumeni syndrome.² Speak to your healthcare provider to learn more about treatment options for specific cancers. 

FAQs

How can I prevent Li-Fraumeni syndrome?

Preimplantation genetic testing is a type of assisted conception which examines the genes of embryos in the laboratory. Only unaffected embryos are transferred into the uterus of the birthing parent, thus preventing Li-Fraumeni syndrome from being passed to offspring.⁸

How common is Li-Fraumeni syndrome?

Li-Fraumeni syndrome is a rare condition. One study estimated that the condition affects somewhere between 1 in 3555 and 1 in 5476 people.⁹

Who is at risk of Li-Fraumeni syndrome?

People with an affected first-degree relative have a 50% risk of having Li-Fraumeni syndrome.² Speak to a genetic counsellor about your level of risk if someone otherwise related to you is affected.

What can I expect if I have Li-Fraumeni syndrome?

If you have Li-Fraumeni syndrome, you have at least a 70% chance of developing cancer during your lifetime if you are AMAB. If you are AFAB, your risk is at least 90%. You may choose to undergo cancer surveillance and/or risk-reductive surgery to manage your risk.²

When should I see a doctor?

See a doctor if someone in your family has been diagnosed with Li-Fraumeni syndrome, or if several members of your family have developed cancer at a young age. 

Summary

Li-Fraumeni syndrome is a rare genetic cancer syndrome caused by a mutation (change) in the TP53 gene. Those with Li-Fraumeni syndrome have an increased risk of cancer compared with the general population. The risk of breast cancer, adrenocortical tumours, CNS tumours, osteosarcoma and soft-tissue sarcomas are particularly high. 

Li-Fraumeni syndrome can be diagnosed clinically or through genetic counselling. A genetic counsellor can help you understand your risk if you have an affected relative, and to process the various implications of undergoing testing yourself. Those with an affected parent are at 50% risk of passing the condition to their children, but Can be prevented with preimplantation genetic testing . 

Some people with Li-Fraumeni syndrome choose to undergo regular cancer surveillance and/or surgery to reduce their risk of cancer. Cancer is treated in the same way as it is in the general population, although it is best to avoid radiation therapy because this can increase the risk of subsequent tumours.