Course:MEDG550/Student Activities/Li-Fraumeni Syndrome
Li-Fraumeni Syndrome (LFS) is a genetic condition that greatly increases the risk of developing cancer. Our bodies are made up of tiny cells, like a sandcastle is made up of millions of grains of sand. Our cells have the ability to reproduce themselves as needed, and to die when they are old or damaged. Cancer occurs when cells become abnormal and start growing uncontrollably. The affected organ accumulates too many abnormal cells, losing its ability to function normally. Those with LFS are more prone to cancer compared to an unaffected individual. In fact, many people with LFS will develop more than one type of cancer in their lifetime.[1]
Who is Affected by Li-Fraumeni Syndrome?
It is estimated that LFS affects 1 in 5,000 to 1 in 20,000 people worldwide. LFS affects both males and females equally, and it is not limited to particular ethnic groups. In some cases, individuals with LFS may have affected family members but it can also be seen in individuals without a family history of LFS.
What Does Li-Fraumeni Syndrome Look Like?
The types of cancer that are most often seen in individuals with LFS are:[2]
- Breast cancer
- Soft tissue cancers (includes cancers of muscle, fat and nerves)
- Brain cancer
- Adrenal cancer (cancer of the adrenal glands - an organ that sits on top of each kidney)
- Bone cancer
Some other, less common, cancers associated with LFS:[3]
- Hematological cancer (blood cancer)
- Lung cancer
- Melanoma (a type of skin cancer)
- Colon cancer (cancer of the large intestine)
- Pancreatic cancer
- Kidney cancer
- Thyroid cancer
- Ovarian cancer
- Testicular cancer
- Prostate cancer
What Causes Li-Fraumeni Syndrome?
Each cell in our body contains DNA. Our DNA is made up of genes, which contain the recipes for how we are made and how we function day to day. All of us have the same set of genes or recipes. However, the specific ingredients of these recipes can vary from one person to another, which is what makes us all unique. Sometimes these differences can be harmful and can have health consequences. These differences are what are referred to as mutations.
LFS is most commonly caused by a mutation in a gene called TP53. TP53 is a gene that is involved in protecting the body against the formation of cancer. When there is a change in this gene, the body has lost one of its main defense mechanisms against cancer. This is why people with LFS are more likely to develop cancer.
It is important to note that not everyone with a TP53 mutation is guaranteed to develop cancer. However, the risks are significantly higher than that of the general population. Individuals with LFS have a 50% chance of developing cancer by the age of 40, and a 90% chance of developing cancer by the age of 60.[4] Females have a higher risk of cancer, as they are more likely to develop breast cancer than men.[5]
How is Li-Fraumeni Syndrome Inherited?
LFS is a hereditary condition, meaning that the cancer risk can be passed down from generation to generation in a family. LFS is inherited in what is called an autosomal dominant manner. Each individual has two copies of the TP53 gene, one from their mom and one from their dad. Autosomal dominant means that if one of these two copies has a mutation, this is enough to cause LFS. Most people with LFS will have inherited a non-working copy of TP53 from a parent who is also affected by LFS. However, LFS is not always inherited. It is estimated that 7-20% of people with LFS have a brand new TP53 mutation that is not seen in either parent.[6] These are referred to as de novo (new) mutations.
Regardless of whether a person inherits a mutation or has a new mutation, those with LFS can either pass on their working copy of TP53, or their non-working copy to their children. In other words, affected individuals have a 50% chance of having a child affected by LFS.
How is Li-Fraumeni Syndrome Diagnosed?
Given that cancer is typically seen in older individuals, cancer occurring in children and young adults is suggestive of a hereditary cancer condition, LFS being one of them. LFS may be suspected in individuals with a personal or family history of LFS-related cancers. Genetic testing may be available for people to learn whether they have a TP53 mutation. Testing can be used to confirm or deny a suspected LFS diagnosis.
What Do I Do if I Have Li-Fraumeni Syndrome?
Treatment
There is currently no cure for LFS and no medication that can prevent cancer development.
Management
As there is no cure for LFS, medical management of affected individuals involves regular cancer screening. The aim of this approach is to detect cancer in its early and more treatable stages. The following screening recommendations are general. Individuals are encouraged to consult with their doctor for personalized recommendations based on their personal and family history with LFS. Screening typically looks for the more common forms of cancer seen in LFS. In brief, the screening recommendations are as follows:[7]
General Assessment
- Complete physical exams every 3-4 months from birth-age 18
- Complete physical exams every 6 months from age 18 onwards
Breast Cancer
- Self-examination of breasts (assessing for lumps or changes) every month starting at age 18
- Physical breast exam by a doctor every 6 months starting at age 20-25
- Annual breast scans (mammograms) from age 20-75
- Consider risk-reducing breast removal (mastectomy)
Soft Tissue & Bone Cancer
- Annual whole-body scan (MRI) starting at birth
Brain Cancer
- Annual brain scan (MRI) starting at birth
Blood Cancer
- Blood work every 3-4 months starting at birth
Adrenal Cancer
- Abdominal scan (ultrasound) every 3-4 months from birth-age 40
Colon Cancer
- Bowel exam (colonoscopy) every 2 years starting at age 25
Skin Cancer
- Annual skin exam starting at age 18
Genetic Counselling
LFS is a condition that can physically, emotionally and socially impact individuals and their families. Genetic counsellors are specialized health care professionals that can support patients with LFS and help them to adapt to life with this condition. They can provide education on LFS, assess a person's risk based on a family history, explore the option of genetic testing, interpret medical information and provide support to individuals to help them navigate a diagnosis.
Genetic Testing
Individuals with a personal or family history of LFS-related cancers may qualify for genetic testing. Genetic testing involves taking a blood or saliva sample, from which the TP53 gene is analyzed. The spelling of the TP53 gene is compared to a dictionary of sorts to determine whether it contains a spelling mistake, or mutation. The detection of a TP53 mutation can help to confirm an LFS diagnosis. The decision to pursue genetic testing is highly personal. A diagnosis such as this one is life changing, not only for an affected individual, but also for their family. Given what we know about the inheritance pattern of LFS, a sibling or parent of an affected person has a 50% chance of having the same TP53 mutation. From a medical perspective, if genetic testing finds a TP53 mutation, this information may be helpful for a doctor to make the appropriate screening recommendations. Individuals considering genetic testing are strongly encouraged to see a genetic counsellor to weigh the pros and cons before making their decision.
Family Planning
Individuals with LFS have a 50% chance of passing it onto their children. Options exist for parents wanting to find out about an LFS diagnosis in advance, or those wanting to have an unaffected child.
During pregnancy, genetic testing can be done on a fetus to determine whether the baby will have LFS. Cells from the fetus are retrieved using one of two procedures: amniocentesis or chorionic villus sampling. If a TP53 mutation is found in the fetus, parents can use these results to either prepare to have an affected child or to end the pregnancy. These procedures have risks and benefits that are important to discuss with a genetic counsellor.
Parents can opt for genetic testing on embryos before a pregnancy has even started, in a process called preimplantation genetic diagnosis (PGD). A woman's eggs are removed and fertilized to form what is called an embryo. This form of fertilization is called in-vitro fertilization because it is done outside of the body, in a laboratory. Approximately 50% of the resulting embryos will have a TP53 mutation, and the other 50% will not. To distinguish the two, cells from each of these embryos can be tested for a TP53 mutation. Parents can then choose to become pregnant with an embryo that does not have the mutation. PGD is done to ensure that a child of an affected parent does not inherit LFS. Alternatively, parents can choose to become pregnant naturally, without any genetic testing. This is a complex decision with several financial and emotional factors to consider. A genetic counsellor can help to review these options to help a couple decide what is the best fit for them.
Key Psychosocial Considerations, Needs, and Interventions
Impact of Intensive, Long-Term Screening
The intensive, long-term screening recommended for LFS surveillance can be lead to more worry, exhaustion, or distress for some, depending on their situation. These might be related to challenges getting to, or planning the screening, or it may be related to worries about the screening itself[8].
However, others may experience some more positive emotions with screening[8]:
- Helped individuals with LFS feel in control and made them feel more safe
- Made LFS feel more 'livable' because action was being taken
- Reduced anxiety or worry
- Feelings of empowerment, positivity, and being proactive
It's possible for individuals to sometimes feel more positive or more negative, or both at the same time, which can be really difficult to understand and process. These feelings can also change depending on many factors as well, and this is important to be aware of.
The following has been shown to make the screening process less burdensome on individuals with LFS[8]:
- Health care providers taking into consideration the difficulties associated with screening (eg. emotional, logistical, etc.)
- Health care providers clearly explaining the risks, benefits and limitations of the screening being offered. This can help to address the anxiety of a false-positive or the false hope of a false-negative.
Family Dynamic of Diagnosis
While some emotions that arise with an LFS diagnosis are shared between many, there may be differences between individuals with LFS who are the first to be diagnosed with LFS in their family compared to those who are aware they are at risk for LFS because others in their family have LFS. Individuals who are the first to have the diagnosis may be shocked, confused and have a lack of understanding. Individuals who have other family members with LFS may be grieving losses, or be immediately worried about other family members, like their children[8]. These feelings need to be taken into consideration and some may benefit from seeking help from a professional, like a cancer therapist, counsellor or psychologist.
Unique Psychological Burden of LFS
An LFS diagnosis leads to a unique, complicated and difficult burden of emotions. Some that are commonly experienced are[8]:
- Ongoing loss, grief and bereavement
- Worrying about mortality
- Anticipating loss of family members with LFS
- Anticipating a cancer development
- Feeling different than other families
Other than seeking help from a cancer counsellor or psychologist, many patients with LFS benefit from using support systems to connect with other. Social support systems, like friends or community groups, can improve mood, help to feel 'normal', help to build, or rebuild identity and provide comfort with crises and loss. Supports that are well informed about LFS are of particular importance as they can help reduce stress and anxiety surrounding the medical part as well[8].
Patient Resources
Additional Information & Support Groups
Li-Fraumeni Syndrome Association
Genetic Counselling
If you are interested in finding a genetic counsellor near you, please visit:
Canadian Association of Genetic Counsellors (Canada)
National Society of Genetic Counselors (United States)
References
- ↑ Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li‐Fraumeni syndrome cohort. Cancer. 2016;122:3673-3681.
- ↑ Li FP, Fraumeni JFJ, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer research (Chicago, Ill.). 1988;48:5358-5362.
- ↑ Nichols KE, Malkin D, Garber JE, Joseph F. Fraumeni J, Li FP. Germ-line p53 Mutations Predispose to a Wide Spectrum of Early-onset Cancers. Cancer Epidemiology Biomarkers & Prevention. 2001;10:83-87.
- ↑ Lustbader ED, Williams WR, Bondy ML, Strom S, Strong LC. Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients. American journal of human genetics. 1992;51:344-356.
- ↑ Wu C, Shete S, Amos CI, Strong LC. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-fraumeni syndrome. Cancer research (Chicago, Ill.). 2006;66:8287-8292.
- ↑ Chompret A, Brugieres L, Frebourg T, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. British journal of cancer. 2000;82:1932-1937.
- ↑ Kratz CP, Achatz MI, Brugières L, et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clinical cancer research. 2017;23:e38-e45.
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Barnett, M (Jul 2021). "Psychosocial interventions and needs among individuals andfamilies with Li-Fraumeni syndrome: A scoping review". Clinical Genetics.