Li-Fraumeni syndrome

This page was reviewed under our medical and editorial policy by

Eric Fowler, MS, LCGC, Manager, Clinical Genetics, Western Region & Licensed Certified Genetic Counselor

This page was reviewed on January 10, 2022.

Li-Fraumeni syndrome (LFS) is a hereditary genetic condition that increases the risk for cancer. Families whose members have this syndrome face a higher risk of developing cancers across several generations and at younger ages.

The most common types of cancer found in LFS families include osteosarcoma (bone cancer), soft tissue sarcoma, acute leukemia, premenopausal breast cancer, brain cancer, and adrenal cortical tumors. However, other types have been linked to LFS, including stomach, lung, pancreatic and colon cancers.

What causes LFS?

LFS is most often linked to an alteration in a gene called TP53. Some families with LFS also have mutations in the gene called CHEK2, but it is unclear if mutations in the CHEK2 gene actually lead to LFS.

TP53 gene is the genetic blueprint for a protein called p53, which stops tumors from growing. The TP53 gene is often referred to as the “guardian of the genome.” When there is a mutation in TP53, the blueprint is flawed. This, in turn, causes the creation of an imperfect p53 protein.

Generally, every cell in the body has two copies of each gene, one from each parent. A person needs only one inherited mutation in the TP53 gene to develop LFS. In fact, most people with LFS have one normal copy of TP53 and one mutated copy, most often passed down from a parent affected by LFS.

However, according to the American Society of Clinical Oncology, 20 percent of LFS patients have no family history of LFS. This mean that the mutation was not inherited from a parent but these patients develop a new mutation.

How is LFS diagnosed?

Li-Fraumeni syndrome is diagnosed if a patient has a genetic test that shows a mutation in the TP53 gene or meets all three of the classical clinical criteria listed below:

  • A diagnosed sarcoma before age 45 years
  • A parent, sibling or child (a first-degree relative) who is diagnosed with any type of cancer before age 45 years
  • A first-degree (parent, sibling or child) or second-degree (grandparent, grandchild, aunt, uncle, niece, nephew, half-sibling) relative diagnosed with any cancer before reaching 45 years old or a sarcoma at any age

LFS may be suspected in a patient who develops hypodiploid acute lymphoblastic leukemia (ALL) before age 21 years or shows TP53 changes in tumor tissue testing.

Another method is the Chompret Criteria. An LFS diagnosis may be suspected if the patient has a personal and family history that meets one of these four points:

  • Diagnosed with a tumor that falls within the LFS spectrum before the patient reaches 46 years old, such as premenopausal breast cancer, soft tissue sarcoma, adrenocortical tumor, central nervous system tumor or osteosarcoma; plus at least one first- or second-degree relative with an LFS tumor before age 56 (not breast cancer if patient has breast cancer) or multiple tumors
  • Multiple tumors other than multiple breast tumors, with at least two of the tumors falling within the LFS tumor spectrum and the first one developing before the patient turned 46 years old
  • An adrenocortical carcinoma or choroid plexus tumor or rhabdomyosarcoma of embryonal anaplastic subtype, regardless of family history
  • Breast cancer before a woman turns 31 years old

From here, testing such as single-gene testing or a multigene panel may be done.

Cancer screening

It is not possible to correct the mutation in the TP53 gene, so attention focuses on rigorous monitoring for signs of cancer, called cancer surveillance. These screenings are extremely important for people with LFS (or suspected LFS) because the lifetime cancer risk is ≥70 percent for men and ≥90 percent for women, according to a GeneReviews article.

For many types of cancer, treatment is typically more successful the earlier it is found. A StatPearls report outlines the important screenings used to look for early signs.

  • Physical exams every 3-4 months from birth to age 18 and every 6 months starting at age 18
  • Prompt evaluations for new or unexplained symptoms
  • Yearly whole-body magnetic resonance imaging (MRI) and yearly brain MRI
  • Ultrasounds (abdominal and pelvic) every three to four months for children and teens and yearly for adults
  • Breast cancer monitoring, including monthly breast self-examination; twice-yearly breast exams between the ages of 20 and 25; and yearly breast MRI between the ages of 20 and 30. At age 30, yearly mammograms and breast MRI until the age of 75.
  • Colonoscopy and upper endoscopy every two to five years, beginning at age 25 or five years before the age at which the youngest family member developed colon cancer
  • Yearly neurologic exams at all ages and dermatologic exam starting at the age of 18 years

Treating LFS

A patient’s care team may include a geneticist, an internist, an oncologist and a radiologist—each dedicated to showing the person how best to manage various aspects of care. Psychological health is important, too—people with LFS often deal with anxiety and depression because of the uncertainty surrounding the condition. Patients should ask their doctor, or a therapist or psychiatrist, about emotional assistance.

Regardless of whether a cancer patient has LFS, the treatment options are likely to be the same.

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