TP53 Gene Mutations
Li-Fraumeni Syndrome (LFS)
What does it mean to have a TP53 gene mutation, and a diagnosis of Li-Fraumeni Syndrome (LFS)?
People with mutations in the TP53 gene have a condition called Li-Fraumeni Syndrome, or LFS. People with LFS have a high risk for many different types of cancer. These cancers can develop at young ages, including childhood. TP53 mutations are often found in women who have developed breast cancer under age 30. Many people with LFS will be diagnosed with cancer 2 or more times during their lifetime.
Many of the cancers that are seen in people affected by LFS are quite rare for people who do not have LFS. Some of these cancers include: cancers of the adrenal gland, the choroid plexus (a part of the brain), and bone and muscle sarcomas. In addition to these unusual cancers, people with LFS have higher risks for more common cancers, like female breast cancer, colorectal cancer, and leukemia.
What can be done to protect people with LFS from cancer?
The National Comprehensive Cancer Network (NCCN) provides recommendations for lowering the risk of cancer in men and women with LFS. These recommendations include starting screening at younger ages and having screenings more often. For example, colonoscopies to check for colon cancer should begin at age 25 or younger, and should be done every 2 to 5 years. Women with LFS should begin breast screening in their 20‚Äôs, and should have MRIs instead of, or in addition to, mammograms. The risk of breast cancer in women with LFS is very high, and in some cases it may even be reasonable to consider surgery to remove the breasts before cancer can develop.
As mentioned earlier, people with LFS have a high risk for many different types of cancer, even in childhood. Some of these cancers are hard to detect. Research is now being done to develop ways to find these cancers as early as possible, when treatment is most likely to be successful. Available results from these studies have been encouraging. For more information about research studies, talk to your provider.
The gene that is altered in people with LFS, the TP53 gene, helps to repair DNA damaged by radiation. People with defects in the TP53 gene are more sensitive to radiation. Therefore, people with LFS should avoid exposure to radiation except when absolutely necessary.
Because LFS is associated with many different cancer risks, it is recommended that people with mutations in the TP53 gene be cared for by healthcare professionals with experience in treating this condition. A list of centers that have specialized knowledge and experience with LFS is available within our Support Organizations pages.
Associated Syndrome Name: Li-Fraumeni Syndrome (LFS)
TP53 Summary Cancer Risk Table
|Cancer||Genetic Cancer Risk|
|Female Breast||High Risk|
TP53 gene Overview
- Individuals with germline mutations in TP53 have a condition called Li-Fraumeni Syndrome (LFS).
- Individuals with LFS have a high lifetime cumulative risk for a wide spectrum of cancers and for developing multiple primary tumors. Cancer risk is heavily biased towards younger ages, and individuals with LFS often develop cancer at early ages, with the majority of cancers diagnosed under age 45.
- The most common cancers diagnosed in patients with LFS are premenopausal female breast cancer, soft tissue and bone sarcomas, adrenocortical carcinoma and brain tumors. However, the risk for a diverse group of other cancers may also be increased as detailed in the Cancer Risk Table below.
- The overall lifetime cancer risk for women is higher than that for men. This is mostly due to the very high risk for female breast cancer compared with the 12.5% lifetime risk for breast cancer in women in the general population of the United States. Male breast cancer risk is not thought to be increased.
- When possible, individuals with LFS are advised to avoid therapeutic radiation therapy for the treatment of cancer, as this can increase the likelihood of additional malignancies.
- Although the risk for cancer in patients with LFS is very high, it may be possible to reduce this risk with appropriate medical management. Guidelines for the management of patients with LFS have been developed by the National Comprehensive Cancer Network (NCCN) and the American Association for Cancer Research (AACR). These are listed below. Since LFS is a rare and complex condition, it is recommended that patients with TP53 mutations and a diagnosis of LFS be managed by a multidisciplinary team with experience in the prevention and treatment of the many malignancies for which these patients are at risk.
TP53 gene Cancer Risk Table
|Cancer Type||Age Range||Cancer Risk||Risk for General Population 4|
|Overall Cancer Risk (male)||To age 55, 6||14%-22%||0.1%|
|To age 206||25%||0.4%|
|To age 506||60%||3.4%|
|To age 706||95%||20.3%|
|Overall Cancer Risk (female)||To age 55, 6||3%-22%||0.1%|
|To age 206||15%||0.3%|
|To age 506||92%||5.4%|
|To age 706||100%||19.2%|
|Overall Cancer Risk (male and female)||Risk for a second primary cancer within 10 years of a first cancer diagnosis6||50%||NA|
|Female Breast||To age 706||85%, with a strong tendency towards very young ages of diagnosis - the large majority of cases occurring before age 45||7.1%|
|Other - including Adrenocortical Carcinoma, Choroid Plexus Carcinoma, Soft Tissue Sarcoma, Bone Sarcoma, and Brain||To age 801, 2, 5, 6||Greatly increased risk, with a strong tendency towards young ages of diagnosis - sometimes in childhood||NA|
|Colorectal||To age 801, 7||Elevated risk, with a strong tendency towards young ages of diagnosis - the median age of diagnosis is estimated to be 41||3.0%|
|Other - including non-Melanoma Skin, Lung, Leukemia, Lymphoma, Esophageal, Neuroblastoma, Thyroid, and Kidney||To age 801, 2||Elevated risk||NA|
|Gastric||To age 802, 5, 6||Elevated risk, with a tendency towards young ages of diagnosis.||0.6%|
|Ovarian||To age 802, 5, 6||Possibly elevated||1.0%|
|Pancreatic||To age 802, 5, 6||Possibly elevated||1%|
|Prostate||To age 802, 5, 6||Possibly elevated||10.9%|
|Endometrial||To age 802, 5, 6||Possibly elevated||2.4%|
|Melanoma||To age 802, 5, 6||Possibly elevated||1.6%|
TP53 Cancer Risk Management Table
The overview of medical management options provided is a summary of professional society guidelines as of the last Myriad update shown on this page. The specific reference provided (e.g., NCCN guidelines) should be consulted for more details and up-to-date information before developing a treatment plan for a particular patient.
This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.
|Cancer Type||Procedure||Age to Begin||Frequency|
|Overall Cancer Risk||Provide education about the signs and symptoms of cancer1||As needed||As needed|
|Female Breast||Breast awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness.1, 8||18 years||NA|
|Clinical breast examination1, 8||20 years, or at the age of the earliest diagnosis in the family if under age 20.||Every 6 to 12 months|
|Breast MRI with contrast and/or Mammography with consideration of tomosynthesis1, 8||Age 20 for MRI (preferred) or mammography. Age 30 for both MRI and mammography.||Annually|
|Consider risk-reducing mastectomy.1, 8||Individualized||NA|
|Other including Adrenocortical Carcinoma, Sarcomas, Brain tumors, Leukemia, Lymphoma, and other cancers, especially those for which there is a past diagnosis in the family.||Comprehensive physical and neurological examination1, 8||From birth||Every 3 to 4 months (from birth to age 18) and every 6 to 12 months from age 18|
|Whole body MRI, including brain1, 8||From birth||Annually|
|Abdominal and pelvic ultrasound1, 8||From birth||Every 3 to 4 months (from birth to age 18) and annually from age 18|
|Colorectal||Colonoscopy1, 8||25 years, or 5 years younger than the earliest colorectal cancer in the family, whichever comes first||Every 2 to 5 years|
|Other including Ovarian, Endometrial, Prostate and Pancreatic cancer.||Comprehensive physical and neurological examination1, 8||From birth||Every 3 to 4 months (from birth to age 18) and every 6 to 12 months from age 18|
|Whole body MRI, including brain1, 8||From birth||Annually|
|Gastric||Upper endoscopy1, 8||25 years, or individualized to a younger age based on family history||Every 2 to 5 years|
|Melanoma||Skin examination1, 8||18 years||Annually|
Information for Family Members
The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the TP53 gene.
A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.
Approximately 7%-20% of individuals with LFS have not inherited the TP53 mutation from a parent. In these cases the mutation has developed spontaneously in that individual (a de novo mutation). Once this occurs, the children of that individual are each at 50% risk of inheriting the mutation.2
Since TP53 mutations carry a very high risk for cancer in young children, it is important that consideration be given to the possibility of genetic testing and screening at very young ages.
Parents who are concerned about the possibility of passing on a TP53 mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).1
- Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 1.2018. October 3. Available at http://www.nccn.org.
- Schneider K, et al. Li-Fraumeni Syndrome. 2013 Apr 11. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Available from http://www.ncbi.nlm.nih.gov/books/NBK1311/ PMID: 20301488.
- Villani A, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016 17:1295-305. PMID: 27501770.
- Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/faststats. (Accessed on 1-2-2017)
- Bougeard G, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015 33:2345-52. PMID: 26014290.
- Mai PL, 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. PMID: 27496084.
- Wong P, Vet al. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology. 2006 130:73-9. PMID: 16401470.
- Kratz CP, et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin Cancer Res. 2017 23:e38-e45. PMID: 28572266.