Li-Fraumeni syndrome

What Does It Mean to Test Positive for a TP53 Mutation?

Mutations in TP53 are associated with Li-Fraumeni syndrome (LFS). Individuals with LFS have a significantly increased risk of developing many types of cancers, often in early childhood or young adulthood.

What Are the Cancer Risks Associated with a TP53 Mutation?

Nearly 100% of women and 75% of men who have a mutation in TP53 will develop cancer in their lifetime. Individuals with a TP53 mutation are also at risk for multiple cancer diagnoses in their lifetime.

Cancer Risks and Average Ages of Onset

The majority of individuals with LFS who receive a cancer diagnosis are under the age of 45. Although LFS can cause many different cancer types, the most common types of cancers seen in TP53 mutation carriers include the following:

  • Breast cancer: Women who are TP53 mutation carriers have an increased risk of developing pre-menopausal breast cancer, with an average age of diagnosis of 33.
  • Sarcoma: TP53 mutation carriers have an increased risk of developing sarcoma, a type of cancer that develops from cells related to connective tissue including cancers related to muscles, nerves, bones, and fat. Sarcomas can occur in children and adults with TP53 mutations and are most often diagnosed before age 50.
  • Adrenocortical carcinoma: TP53 mutation carriers have an increased risk of developing adrenocortical carcinoma, a rare type of cancer that develops on the outer tissue layer of the adrenal glands (a small organ on top of each kidney that produces steroid hormones, adrenaline, and other hormones that control heart rate, blood pressure, and other body functions). Adrenocortical carcinomas can develop in both children and adults.
  • Brain tumor: TP53 mutation carriers have an increased risk of developing brain cancer. Tumors can occur in childhood or adulthood, with an average age of diagnosis of 16.

What Cancer-Screening and Risk-Reducing Options Are Available?

Individuals who are positive for a TP53 mutation are encouraged to work with a multidisciplinary team of specialists to manage increased cancer risks.

For Men and Women

  • Physical examination every 6 to 12 months is recommended for children and adults.
  • An annual dermatologic examination is recommended starting at age 18.
  • Colonoscopies and upper endoscopies are recommended beginning at age 25 or five years before the earliest colon cancer diagnosis in the family and repeated every two to five years thereafter.
  • Annual whole-body MRIs are recommended. If this screening is not available, TP53 mutation carriers may consider a clinical trial or an alternative comprehensive screening method.
  • When possible, cancer treatment with radiation should be avoided.
  • Additional screening may be recommended based on family history.

For Women

  • Beginning at age 18, women should be educated regarding breast self-awareness, which includes being familiar with one's breasts and promptly reporting any changes. Monthly breast self-examinations may facilitate breast awareness.
  • Beginning at age 20 or earlier, based on family history, clinical breast examinations are recommended every 6 to 12 months.
  • Beginning at age 20, breast imaging with MRIs and/or mammograms is recommended every 6 to 12 months:
  • For women ages 20 to 29, annual MRI is the preferred screening method.
  • For women ages 30 to 75, annual MRIs and mammography are recommended, with consideration of 3D mammograms (tomosynthesis).
  • For women over age 75, breast cancer screening can be considered on an individual basis.
  • Bilateral mastectomy (surgical removal of both breasts) may significantly reduce breast cancer risk in mutation carriers.

What Is the Chance That Family Members of TP53 Mutation Carriers Have the Same Mutation?

TP53 mutations are passed down in a family. This means that family members of TP53 mutation carriers may have the same mutation and may also be at increased risk of developing cancer. Up to 20% of the time, a sporadic genetic mutation occurs in a single family member, which means an individual could be the first person in a family to have a TP53 mutation. In either case, it is important for TP53 mutation carriers to discuss genetic test results with family members.

  • Close blood relatives of TP53 mutation carriers, such as parents, siblings, and children, have up to a 50% chance of having the same mutation.
  • For individuals who are determined to be the first affected member of a family, testing is still indicated for biological children who have a 50% chance to inherit the TP53 mutation.
  • Distant relatives, such as aunts, uncles, grandparents, and cousins, also have a chance of having the same TP53 mutation.
  • A physician or a genetic counselor can help mutation carriers determine whether the mutation was more likely to have been inherited from the maternal or paternal side of the family. In general, the mutation will only be inherited from one side of the family, and it is more likely to be inherited from the side of the family that has a strong history of cancer.

Genetic testing of family members can help determine which family members have an increased risk for cancer and may benefit from the screening and/or risk-reduction options discussed above. Family members who test negative for a known familial TP53 mutation likely have the same risk for cancer as the general population and can follow the general population's screening guidelines.

What Else Should TP53 Mutation Carriers Know?

Rarely, a TP53 mutation is identified in an individual who does not have a personal or family history of cancer consistent with a diagnosis of LFS. This can occur due to somatic mosaicism in which cells in the blood or saliva used for genetic testing have a TP53 mutation; however, that same mutation is NOT present throughout the body and may not be associated with the high risks of cancer described above. In these situations, additional genetic testing of fibroblasts (skin tissue) and/or family members may be necessary to further clarify the result and to determine appropriate medical management.

Mutation carriers who are interested in options to prevent passing their mutation to future children may wish to consider preimplantation genetic diagnosis (PGD). PGD is a procedure that involves in vitro fertilization (IVF) and can determine if an embryo carries the genetic mutation present in a family. Determining which embryos carry a family mutation may allow a mutation carrier to prevent the condition from being passed to future children. The decision to undergo PGD is personal. Mutation carriers and their family members can talk with a healthcare provider to learn more about their reproductive options for mutation carriers.