Li-Fraumeni syndrome is a hereditary cancer syndrome.

What is Li-Fraumeni syndrome?

Li-Fraumeni syndrome (LFS) is a hereditary condition associated with higher risks of a range of childhood- and adult-onset cancers. This condition can be passed down in a family and is caused by a faulty (disease-causing) TP53 gene.

The most common types of cancers associated with LFS include sarcomas (cancers arising from connective tissue) and:

• Brain cancer
• Leukaemia
• Cancer of the adrenal cortex (the outer layer of the adrenal glands)
• Breast cancer
• Sarcomas (cancer arising from connective tissue)
• Bone cancer (osteosarcoma)

How common is LFS?

The estimated frequency of LFS ranges between one in 5,000 to 20,000 people. These rates may change as more information is known.

What is genetic testing?

Genetic testing is offered to individuals where a hereditary cause of their personal and/or family history of cancer is suspected.

Genes contain the instructions that our body reads to carry out different functions. Genetic testing involves analysing your genes to understand if there are faults (i.e., mutations) that may increase the risk of diseases like cancer.

How is genetic testing done?

• Genetic testing is typically a one-time blood test.
• If a blood sample cannot be taken, other sample sources (e.g., skin or saliva) may be used.

Hereditary cancer accounts for up to 10% of all cases of cancer.

What are the possible results of genetic testing?

There are 3 types of results you may receive:

What are the cancer risks associated with LFS?

The risk of other cancers including leukaemia, Wilms tumour, neuroblastoma, and lung, colorectal, stomach and pancreatic cancers may also be increased (risk figures not quantified).

Note: The conditions associated with LFS and their risk estimates may change as more information is available. Published literature may overestimate cancer risks. These figures are based on retrospective analysis which may be biased towards families with an excess of cancer diagnoses.

Note: The conditions associated with LFS and their risk estimates may change as more information is available. Published literature may overestimate cancer risks. These figures are based on retrospective analysis which may be biased towards families with an excess of cancer diagnoses.

How is LFS inherited?

LFS follows a dominant inheritance pattern. This means that individuals who have one faulty copy of the TP53 gene have an increased risk of cancer. It can affect both males and females.

Everyone has 2 copies of each gene in their body’s cells:

• 1 copy comes from our father
  
• 1 copy comes from our mother

A parent with a faulty gene(s) has a 50% chance of passing down their faulty gene(s) to their children. A child, sibling or parent of a family member with a faulty gene(s) has a 50% chance of also inheriting the same faulty gene(s). Extended relatives may also inherit the faulty gene(s).

Who should undergo genetic testing for LFS?

You should consider genetic testing if you or your family members meet one or more of the following criteria:

1. Sarcoma diagnosed before the age of 45
2. Sarcoma diagnosed at any age, with a relative diagnosed with cancer before the age of 45 or a sarcoma diagnosed at any age
   
3. Breast cancer diagnosed before the age of 31
4. A LFS-related condition* diagnosed before the age of 46 and a family history of cancer
5. Two or more LFS-related conditions* in the same individual
6. Two or more family members on the same side of the family with a LFS-related condition* before the age of 56
7. Adrenocortical cancer or rhabdomyosarcoma at any age
8. Tumour in the choroid plexus (membrane surrounding the brain) at any age
9. A previously identified faulty TP53 gene in the family
10. A TP53 gene fault identified at high frequency on tumour testing

While LFS may run in families, up to 25% of individuals with LFS may have acquired a faulty TP53 gene at birth (de novo). Therefore, genetic testing may also be offered in the absence of relevant family history and/or if an individual’s personal history is suspicious for LFS.

*LFS-related conditions:

• Soft tissue cancer (sarcoma)
• Bone cancer (osteosarcoma)
• Central nervous system tumour
• Breast cancer (often early-onset)
• Adrenocortical tumour
  
• Leukaemia
• Bronchoalveolar cancer
• Colorectal cancer

How can your genetic test result help you?

1. Personalised management
   Your genetic test result may confirm whether your personal and/or family history is due to a hereditary condition like LFS, and clarify what your lifetime cancer risks may be. This information can be useful for doctors to personalise your medical care to help manage or reduce cancer risks.

   If you have a cancer diagnosis

   • Helps guide important treatment and/or surgical decisions
   • Indicates what other cancers you are at risk of and how to manage these risks

    

   If you are currently cancer-free

   • Helps guide management and relevant screening options for you to detect cancer at its earliest, most treatable stage
   • Helps guide your lifestyle and screening decisions (e.g., unnecessary radiation exposure should be avoided)
     
   • Helps guide decisions regarding relevant cancer risk-reducing interventions (e.g., surgery)
   • Allows individuals with LFS to consider dedicated reproductive options for family planning

    

2. Familial implications
   Your genetic test result can also help you understand if other family members are at risk of LFS. They can subsequently consider their own testing (predictive testing) to clarify their carrier status to determine tumour and cancer risks.
   
   Family members who have inherited the same faulty TP53 gene may be at increased risk of tumours and cancer and can benefit from management options such as screening (to detect tumours and cancer at an early and manageable stage) or surgery (to reduce their risk of cancer).
   
   Family members who did not inherit the faulty TP53 gene can avoid unnecessary screening and worry. Their children will also not be at risk.

What can I do to manage my increased risk of tumours and cancers?

Screening for LFS from birth

Unnecessary radiation exposure for screening or therapeutic purposes should be avoided where possible.

• General assessments
  • Regular physical examinations
  • Full neurological assessments
  • Early reporting of symptoms
• Adrenocortical carcinoma (ACC)
  • Ultrasound of abdomen and pelvis
  • Additional blood tests may be recommended
• Soft tissue and bone sarcoma
  • Ultrasound of abdomen and pelvis
    
  • Whole-body MRI
• Brain tumour
  • Brain MRI

Screening for LFS from the age of 18 onwards

• Breast cancer
  • Breast awareness and self-examination
  • Clinical breast examination
  • Breast MRI
  • Consider hormone therapy (tamoxifen/raloxifene)
• Melanoma
  • Dermatological examination
• Gastric/colorectal cancer
  • Upper gastrointestinal endoscopy and colonoscopy

Your managing doctor(s) will discuss screening recommendations with you in greater detail, which may be tailored based on your medical history. The age and onset of screening may depend on your personal and/or family history of the condition. Screening guidelines may change as more information is known.

Risk-reducing surgery

In some cases, individuals can consider interventions such as surgery to reduce their risk of cancer.

• Breast cancer
  • Bilateral mastectomy: Surgery to remove breast tissue (greatest benefit when performed under the age of 40)

This will be discussed in detail with you by your managing doctor(s). The surgery may reduce the risk of cancer significantly, but does not remove the risk completely.

Lifestyle adjustments

• Avoid smoking
• Avoid excessive alcohol consumption
• Keep a healthy diet and active lifestyle
• Avoid sun exposure and practise sun-smart behaviour such as using sunscreen