Li-Fraumeni Syndrome Overview

Li-Fraumeni syndrome is an inherited condition that significantly increases the lifetime risk of developing several types of cancer, often at a younger age than typically seen in the general population. This hereditary cancer predisposition syndrome is exceedingly rare, affecting approximately one in 20,000 individuals worldwide, although it may be underdiagnosed in some populations.

Individuals with Li-Fraumeni syndrome face a 90% likelihood of developing one or more types of cancer by age 60, with approximately 50% affected by age 40. Almost all females with Li-Fraumeni syndrome develop breast cancer.

Li-Fraumeni syndrome cannot be prevented, but early and consistent cancer screenings and appropriate cancer treatment as needed can limit its impact on daily life. Scientists are actively investigating new ways to identify and treat the cancers associated with this highly uncommon condition.

What types of cancer are linked to Li-Fraumeni syndrome?

Both children and adults with Li-Fraumeni syndrome are strongly predisposed to developing multiple cancers, most notably:

• Soft tissue and bone sarcomas, such as rhabdomyosarcoma and osteosarcoma
• Breast cancer
• Brain tumors, such as glioblastomas and medulloblastomas
• Adrenocortical carcinoma, a rare cancer of the adrenal glands
• Acute lymphoblastic leukemia (ALL) and other blood cancers

Li-Fraumeni syndrome has also been linked to gastric, lung, kidney, thyroid, skin (melanoma), prostate and ovarian cancers, among others.

What causes Li-Fraumeni syndrome?

Li-Fraumeni syndrome is caused by an inherited mutation in the TP53 gene, which normally helps suppress tumor formation and provides instructions for the body’s production of the p53 protein. Often referred to as the “guardian of the genome,” the p53 protein plays a key role in regulating cell division, repairing damaged DNA and initiating cell death (apoptosis) when DNA damage cannot be repaired.

When the TP53 gene is mutated, the resulting p53 protein may lose its ability to control cell growth and repair DNA damage. This can allow abnormal cells to divide uncontrollably, increasing the likelihood of cancer development.

In most cases, a single copy of the mutated TP53 gene—inherited from one parent—is sufficient to cause Li-Fraumeni syndrome. In other words, the mutation is usually inherited in an autosomal dominant pattern. In rare cases, the genetic alteration is not inherited but rather occurs spontaneously (de novo).

What are the risk factors for Li-Fraumeni syndrome?

An individual may be at risk of carrying the inherited TP53 gene mutation that causes Li-Fraumeni syndrome if they have:

• A family history of Li-Fraumeni syndrome or the associated cancers
• A family history of multiple early-onset cancers, particularly sarcomas, breast cancer, brain tumors and adrenocortical carcinoma
• A personal history of more than one cancer

What are the signs and symptoms of Li-Fraumeni syndrome?

Li-Fraumeni syndrome itself does not have specific warning signs. Instead, its symptoms can vary depending on the type of cancer that develops. Possible indicators include:

• Soft tissue sarcomas – Painless lumps and swelling in the limbs or trunk
• Breast cancer – Lumps or changes in breast tissue, often diagnosed before age 30
• Brain tumors – Headaches, seizures, nausea and neurological changes
• Adrenocortical carcinoma – Hormonal imbalances, unexplained weight changes and abdominal pain
• Osteosarcoma – Bone pain, swelling and fractures
• Multiple cancers – More than one primary cancer, sometimes simultaneously or in succession
• Rare or unusual cancers – Tumors uncommon in the general population, such as adrenocortical carcinoma in children
• A family history of cancer – Several relatives with early-onset cancers, particularly the types linked to Li-Fraumeni syndrome
• Aggressive cancer – Rapid and noticeable tumor growth

How is Li-Fraumeni syndrome diagnosed?

Li-Fraumeni syndrome is diagnosed based on a combination of clinical criteria and genetic testing to confirm the presence of a mutation in the TP53 gene. The diagnostic process typically begins with a clinical assessment of the patient’s personal and family medical history. Specifically, the physician will check for patterns consistent with Li-Fraumeni syndrome. Clinical criteria include:

• A sarcoma diagnosed before age 45
• A first-degree relative, meaning a parent, sibling or child, diagnosed with any cancer before age 45
• A first-degree or second-degree relative, meaning a grandparent, aunt/uncle, niece/nephew or grandchild, diagnosed with any cancer before age 45 or a sarcoma at any age

Genetic testing and counseling are often recommended for individuals who meet these clinical criteria or have a strong family history of cancers linked to Li-Fraumeni syndrome. Genetic testing may also be offered to the family members of an individual with a confirmed TP53 mutation. Typically, the testing process involves analyzing a blood or saliva sample for mutations in the TP53 gene. There are three possible outcomes:

• Positive – A mutation was identified in one or more of the genes analyzed. While this result may indicate an increased likelihood of developing cancer, the precise risk level can vary depending on which gene is mutated. Most mutations are not associated with a 100% likelihood of developing cancer.
• Negative – No mutations were identified in the genes analyzed. Therefore, the likelihood of a hereditary cancer predisposition syndrome is significantly reduced.
• Inconclusive – A mutation was identified in one or more of the genes analyzed but there is insufficient evidence to determine whether the genetic alteration increases the risk of cancer. Most inconclusive findings are eventually classified as harmless.

Additionally, if an individual is diagnosed with cancer, a tumor sample may be examined to check for TP53 gene mutations or loss of p53 protein activity, which could indicate an underlying genetic cancer predisposition, such as Li-Fraumeni syndrome.

An early and accurate diagnosis is essential for the effective management of Li-Fraumeni syndrome. Armed with this important information, the patient and their family can take preventive measures, undergo regular screenings and seek specialized care to reduce the risk of cancer development.

How is Li-Fraumeni syndrome treated?

Li-Fraumeni syndrome cannot be treated. Instead, a physician may recommend various preventive and risk-reduction strategies to help the patient manage the associated increase in cancer risk, such as:

• Regular cancer screenings – Frequent screenings, starting at a young age, can be performed for cancers commonly associated with Li-Fraumeni syndrome, including breast cancer, brain tumors and sarcomas.
• Genetic counseling – Family members of an individual diagnosed with Li-Fraumeni syndrome can assess their own risk of inheriting the TP53 mutation and explore testing options.
• Prophylactic surgery – In some cases, preventative surgery may be considered to remove at-risk tissues, such as a prophylactic mastectomy to reduce breast cancer risk.
• Close monitoring – Regular physical examinations, imaging tests and blood work can help detect early signs of cancer.
• Lifestyle modifications – Practicing healthy habits, such as avoiding tobacco use and maintaining a healthy body weight, can help reduce cancer risk.

Benefit from world-class care at Moffitt Cancer Center

At Moffitt, a team of board-certified genetic counselors is available to meet with patients to assess their hereditary risk of cancer. By providing comprehensive information and individualized guidance, we empower our patients to make the right choices for themselves regarding genetic testing.

If you would like to learn more about Li-Fraumeni syndrome, you can request an appointment with a specialist in Moffitt’s Genetic Counseling Clinic by calling 1-888-663-3488 or completing a new patient registration form. We do not require referrals.