Li-Fraumeni Syndrome

Clinical characteristics: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with high risks for a diverse spectrum of childhood- and adult-onset malignancies. The lifetime risk of cancer in individuals with LFS is ≥70% for men and ≥90% for women. Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas. LFS is associated with an increased risk of several additional cancers including leukemia, lymphoma, gastrointestinal cancers, cancers of head and neck, kidney, larynx, lung, skin (e.g., melanoma), ovary, pancreas, prostate, testis, and thyroid. Individuals with LFS are at increased risk for cancer in childhood and young adulthood; survivors are at increased risk for multiple primary cancers.

Diagnosis/testing: The diagnosis of LFS is established in a proband who meets ALL THREE classic clinical criteria and/or has a heterozygous germline pathogenic variant in TP53. Classic clinical criteria:

1. A proband with a sarcoma diagnosed before age 45 years

2. A first-degree relative with any cancer diagnosed before age 45 years

3. A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age

Management: Treatment of manifestations: Routine oncologic management is recommended for malignancies, with the exception of breast cancer, in which bilateral mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast cancer and avoid radiation therapy. Concerns about increased risk for radiation-induced second primary tumors has led to more cautious use of therapeutic radiation in general, but most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits.

Prevention of primary manifestations: Prophylactic bilateral mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 pathogenic variant. Colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Avoidance of sun exposure, tobacco use, and exposure to other known or suspected carcinogens is encouraged.

Surveillance: Comprehensive physical examination and ultrasound of abdomen and pelvis every 3-4 months from birth to age 18 years, annual neurologic exam and whole-body MRI including brain MRI from the time of diagnosis. In individuals 18 years or older, complete physical exam every 6 months, ultrasound of abdomen and pelvis and dermatologic exam annually. Women should have a clinical breast examination every 6-12 months beginning at age 20-25 years, annual breast MRI beginning at age 20-30 years, annual mammogram and breast MRI from age 30 to age 75 years. Upper endoscopy and colonoscopy are recommended every 2-5 years in individuals from age 25 years.

Agents/circumstances to avoid: Minimize exposure to diagnostic and therapeutic radiation; avoid known carcinogens including sun exposure, tobacco use, occupational exposures, and excessive alcohol use.

Evaluation of relatives at risk: It is appropriate to offer genetic counseling and testing to all relatives who are at risk of having a familial TP53 pathogenic variant.

Genetic counseling: LFS is inherited in an autosomal dominant manner. Most individuals diagnosed with LFS inherited a TP53 pathogenic variant from a parent. The proportion of individuals with a de novo germline TP53 pathogenic variant is estimated to be between 7% and 20%. Offspring of an individual with an established diagnosis of LFS (i.e., an individual who meets classic LFS criteria and/or has a heterozygous germline TP53 pathogenic variant) have a 50% risk of inheriting an LFS-causative pathogenic variant and having the cancer risks associated with LFS. Predictive testing for at-risk family members, prenatal testing, and preimplantation genetic testing are possible if a TP53 germline pathogenic variant in the family has been identified.