Li-Fraumeni Syndrome – Indication for Testing and Recommended Surveillance
A germline mutation of the TP53 gene, which causes Li-Fraumeni syndrome, results in a congenital predisposition to the occurrence of malignant tumors, such as pediatric malignancies, breast cancer, bone sarcomas, and others. We bring a summary of indications for testing the pathogenic variant of the TP53 gene according to the recommendations of the National Comprehensive Cancer Network (NCCN) and the surveillance program for carriers of this variant according to the consensus of the current recommendations of the European, American, Japanese, and Australian scientific societies compared to the recommendations of the Czech Oncology Society ČLS JEP.
Li-Fraumeni Syndrome
Approximately 10% of breast cancer cases are associated with the presence of a pathogenic variant of one of the genes with a predisposition to an increased risk of this malignancy. Most commonly, it involves mutations in the BRCA1 and BRCA2 genes. Another such gene is TP53.
Tumor protein 53 (TP53) is a tumor suppressor that controls cell growth and division. It protects cells from genome changes due to DNA damage by suppressing their proliferation or activating apoptosis. The germline pathogenic variant of the TP53 gene in the heterozygous state is associated with a congenital tumor syndrome classically known as Li-Fraumeni syndrome (LFS). It is a rare autosomal dominant hereditary predisposition to malignant diseases including early-onset pediatric cancers, primary soft tissue carcinomas, bone sarcomas, breast carcinoma, adrenal cortex carcinomas, gastrointestinal, lung, pancreatic, prostate cancers, and also leukemia.1
Risk of Malignant Disease in LFS
The cumulative risk of malignant tumor associated with LFS is estimated to be approximately 50% by age 40 and 90% by age 60, with women being at higher risk primarily due to the high incidence of premenopausal breast cancer. The lifetime risk of breast cancer in healthy women carrying the pathogenic variant TP53 is estimated to be 80-90%. Different types of breast cancer can develop in patients with the TP53 pathogenic variant, with the highest increased risk for developing the HER2-positive type.1
Prevalence of LFS in Patients with Breast Cancer
Among breast cancer patients, the proportion of individuals with the germline mutation TP53 ranges from 0.5% in the unselected population to 5-10% in the highly selected population diagnosed with breast cancer at a young age or with a strongly positive family history.1
Indication for Testing the Pathogenic Variant TP53
Various criteria have been proposed for testing the pathogenic variants of TP53.1 According to the latest NCCN recommendations from 2023, testing is appropriate in:2
- Individuals from families with a known occurrence of the pathogenic variant TP53.
- According to classic LFS criteria in patients with sarcoma before age 45 + a direct relative with malignancy before age 45 + another relative in the same branch with malignant disease before age 45 or sarcoma at any age.
- According to Chompret criteria:
- in patients with a tumor from the LFS spectrum (soft tissue sarcoma, osteosarcoma, CNS tumor, breast or adrenal cancer) before age 46 + at least 1 relative of first or second degree with the aforementioned tumors (excluding breast cancer if the proband has breast cancer) before age 56 or with multiple primary tumors at any age;
- in patients with multiple tumors (excluding multiple breast carcinomas), 2 of which are in the LFS spectrum and at least 1 appeared before age 46;
- in patients with adrenal cortex carcinoma, plexus choroideus carcinoma, embryonal anaplastic subtype rhabdomyosarcoma at any age regardless of family history;
- in patients with breast cancer before age 31.
- In pediatric patients with hypodiploid acute lymphoblastic leukemia.
- In individuals with a pathogenic variant TP53 discovered during genomic testing of tumor cells, which could also be detected during germline mutation testing.
Treatment and Monitoring of Breast Cancer Patients and LFS and Their Relatives
According to current recommendations, local-regional radiotherapy is not suitable for breast cancer patients related to LFS due to the risk of developing additional primary tumors. In surgical treatment, mastectomy should be preferred over lumpectomy. It is appropriate to discuss prophylactic contralateral mastectomy with the patient; otherwise, annual screening using MRI is necessary. Whole-body MRI is also recommended within the surveillance of other malignant tumors (see diagram). No data are available on the choice of specific therapy for breast cancer in patients with LFS. However, due to their worse prognosis and risk of additional malignancies, attention should be given to symptoms indicating their occurrence.1
The Czech Oncology Society ČLS JEP recommends the following screening procedures for adults with a pathogenic variant of TP53:3
- Physical examination every 6 months
- MRI of the brain once a year
- Whole-body MRI once a year
- Ultrasound of the pelvis and abdomen once a year
- GFS and colonoscopy once every 2-5 years starting at age 25
- Skin examination once a year starting at age 18
- Breast self-examination starting at age 18
- Physical breast examination once every 6 months starting at age 20
- Breast MRI once a year starting at age 20
- Consider and discuss bilateral preventive mastectomy
Conclusion
The finding of a causal variant in the TP53 gene in a breast cancer patient should be a reason for cascade genetic testing in direct relatives, including children, due to the early detection of the pathogenic variant and early surveillance and prevention. However, future research needs to focus on the long-term clinical and psychological impact of TP53 testing and early detection of its pathogenic variant in children and adolescents. Current recommendations also indicate that every individual with a pathogenic variant of TP53 (healthy or oncologically ill) should be informed that preimplantation genetic testing of embryos and pregnancy planning through IVF and prenatal diagnosis in case of natural conception are available. This can avoid passing the pathogenic variant of TP53 onto future generations.1
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Sources:
1. Blondeaux E., Arecco L., Punie K. et al. Germline TP53 pathogenic variants and breast cancer: a narrative review. Cancer Treat Rev 2023 Mar; 114: 102522, doi: 10.1016/j.ctrv.2023.102522.
2. NCCN Guidelines. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, v.3.2023. NCCN, 2023 Feb 13. Available at: www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
3. Modrá kniha České onkologické společnosti. Chapter 44: Care for healthy carriers of mutations associated with an increased risk of tumors. Masaryk Oncological Institute, 1. 3. 2023. Available at: www.linkos.cz/files/modra-kniha/22/886.pdf
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