What is Li-Fraumeni syndrome?

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline pathogenic variants in the TP53 tumor suppressor gene, characterized by an extraordinarily high lifetime cancer risk (nearly 100% in women, 75% in men) with early-onset diverse malignancies, particularly soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinoma. 1

Genetic Basis and Inheritance

• LFS follows an autosomal dominant inheritance pattern caused by germline mutations in the TP53 gene on chromosome 17, which encodes the p53 protein known as the "guardian of the genome" 2, 3
• The birth prevalence is estimated at approximately 1:3,000 to 1:20,000 in the general population 1
• Germline TP53 mutations were discovered as the sole cause of LFS in 1990 1
• The syndrome can occur with de novo mutations, meaning limited or absent family history does not exclude the diagnosis 1

Core Cancer Spectrum

The "core" LFS cancers that define this syndrome include: 1

• Soft tissue sarcomas (particularly rhabdomyosarcoma) - one of the most common malignancies 2
• Osteosarcoma (bone tumors) - typically presenting at younger ages 2
• Premenopausal breast cancer - the most frequent malignancy in adult women, accounting for 57% of all first cancers by age 60 1
• Brain tumors - including choroid plexus carcinoma, Sonic Hedgehog subtype medulloblastoma, and gliomas 1, 2
• Adrenocortical carcinoma (ACC) - a rare cancer of the adrenal cortex 2

Extended Cancer Spectrum

Beyond core cancers, individuals with LFS develop a wide range of malignancies: 1

• Hematologic malignancies (leukemias, particularly low-hypodiploid acute lymphoblastic leukemia)
• Lung carcinomas
• Gastrointestinal tract cancers (gastric, colorectal)
• Prostate cancer
• Kidney, thyroid, and skin cancers
• Neuroblastoma

Age-Specific Cancer Risks

• Childhood (before age 20): 20-40% cancer risk, predominantly sarcomas, CNS tumors, and adrenocortical carcinoma 1
• Median age at first cancer diagnosis: 33.7 years for women, 45 years for men 1
• By age 70 in women: 54% breast cancer risk, 15% soft tissue sarcoma risk, 6% brain cancer risk, 5% osteosarcoma risk 2
• By age 70 in men: 22% soft tissue sarcoma risk, 19% brain cancer risk, 11% osteosarcoma risk 2

Multiple Primary Cancers

• Approximately 50% of individuals develop simultaneous or metachronous multiple primary cancers during their lifetime 4
• The relative risk of developing a second cancer is 5.3 times higher than the general population, with a cumulative probability of 57% at 30 years after first cancer diagnosis 5
• Survivors of childhood cancers have the highest risk of additional primary cancers (RR = 83.0 for those diagnosed before age 20) 5

Diagnostic Criteria

Classic LFS Criteria (1988)

Requires all three of the following: 1

• One individual with sarcoma diagnosed before age 45
• At least one first-degree relative with any cancer before age 45
• A third family member (first- or second-degree relative in same lineage) with any cancer before age 45 or sarcoma at any age

Chompret Criteria (Updated)

TP53 genetic testing should be strongly considered in these situations: 1

1. Familial presentation: Proband with LFS spectrum tumor before age 46 AND at least one first- or second-degree relative with LFS tumor before age 56 or with multiple tumors
2. Multiple tumors: Proband with multiple malignancies (except two breast cancers), with at least two from LFS spectrum, before age 46
3. Rare tumors: Patients with adrenocortical carcinoma, choroid plexus carcinoma, or embryonal anaplastic rhabdomyosarcoma regardless of family history
4. Early breast cancer: Breast cancer before age 31

Specific Pediatric Cancer Associations

Recent sequencing has revealed LFS plays a significant role in childhood cancers: 1

• 80% of children with diffuse anaplastic rhabdomyosarcoma carry germline TP53 mutations
• 50% of children with adrenocortical carcinoma
• 40% of children with choroid plexus carcinoma
• 40% of children with low-hypodiploid acute lymphoblastic leukemia
• >10% of children with Sonic Hedgehog medulloblastoma
• Up to 10% of children with osteosarcoma

Genotype-Phenotype Correlations

• While certain TP53 variant types correlate with phenotypic variability, it is currently impossible to predict individual phenotype based on genotype alone 1
• "Partially functional" variants in functional assays are associated with lower overall childhood cancer risk (except adrenocortical carcinoma), while NULL variants are enriched in classic LFS versus attenuated presentations 1
• Hotspot variants appear in both classic LFS and attenuated phenotypes, so all confirmed TP53 mutation carriers should receive full surveillance regardless of mutation type 6

Brazilian Founder Mutation

• A specific founder mutation (c.1010G>A; p.R337H) is present in 0.3% of individuals in South/Southeastern Brazil, affecting an estimated 300,000+ Brazilians 1
• The cancer spectrum in these carriers is similar to other TP53 mutations 1

Critical Clinical Implications

• Radiation sensitivity: Individuals with LFS have increased susceptibility to radiation-induced secondary malignancies, requiring avoidance of ionizing radiation (CT scans, therapeutic radiation) whenever possible 1, 7, 6
• Treatment modifications: Women with LFS and breast cancer typically require total mastectomy instead of lumpectomy with radiation 3
• Antineoplastic therapy risks: Cancer treatment itself confers additional risks including sarcomas in radiation fields and therapy-related hematologic malignancies 1

Historical Context

• LFS was first described in 1969 by Frederick Li and Joseph Fraumeni Jr. based on their observation of a unique cancer spectrum in four families with rhabdomyosarcoma index cases 1
• The formal syndrome definition was established in 1988 after analysis of 24 kindreds 1