Li-Fraumeni syndrome (LFS) was first defined by Frederick Li and Joseph Fraumeni Jr. in 1969 based on the history of rhabdomyosarcoma in 4 different families. A patient with LFS:

• Has been diagnosed with a sarcoma before the age of 45 years.
• Has a first-degree relative with any type of cancer who was also diagnosed before age 45.
• Has a third family member (first- or second-degree relative) with a cancer diagnosis in a similar timeline, or a sarcoma at any age. The third member must also be in the same familial lineage as the primary and secondary family members.

LFS follows an autosomal dominant inheritance pattern, caused by germline mutations to the p53 tumor suppressor gene (a TP53 mutation). Loss of this tumor suppressor gene alters cellular ability to protect against environmental stressors and predisposes one to early-onset and high-risk cancers of the brain, adrenal system, soft tissue and bone, blood, breast, lungs, gastrointestinal (GI) tract, kidney, and thyroid. Melanoma has rarely been reported in patients with Li-Fraumeni syndrome, and controversy exists as to whether it is a true syndrome manifestation.

LFS affects both pediatric and adult populations. Osteosarcoma is the most common malignancy in children (30%), and breast cancer is the most common in adults (79% of women with LFS). LFS shows heterogeneity in terms of age of onset and type of malignancy.

Geographically, LFS is highly prevalent in Brazil due to a founder effect mutation. Many individuals of Brazilian descent with LFS have a specific TP53 mutation (p.R337H) that predisposes these individuals to adult papillary thyroid cancer, renal cancer, and lung adenocarcinoma, more so than other carriers of the TP53 gene. This may suggest a variant form of LFS.