Malignancies Associated with Li-Fraumeni Syndrome
Li-Fraumeni syndrome is characterized by five core malignancies—soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumors, and adrenocortical carcinoma—with an expanded spectrum including leukemias, lung cancer, gastrointestinal malignancies, and other early-onset cancers. 1, 2
Core Cancer Spectrum
The most recent guidelines identify the following as core LFS-associated malignancies:
Primary Core Cancers
- Soft tissue sarcomas, particularly rhabdomyosarcoma (with 80% of children with diffuse anaplastic rhabdomyosarcoma carrying TP53 mutations), represent one of the most common malignancies in LFS 1, 2
- Osteosarcomas and bone tumors typically present at younger ages, with up to 10% of childhood osteosarcomas associated with germline TP53 mutations 1, 2
- Premenopausal breast cancer, especially early-onset disease (before age 31 as a standalone criterion, or before age 46 with family history), with women having a 54% lifetime risk by age 70 1, 2, 3
- Brain tumors including gliomas, choroid plexus carcinomas (40% of cases have TP53 mutations), and Sonic Hedgehog subgroup medulloblastomas (>10% of cases) 1, 2
- Adrenocortical carcinoma, a rare malignancy where 50% of childhood cases harbor germline TP53 mutations, warranting testing at any age regardless of family history 1, 2
Hematologic Malignancies
- Acute lymphoblastic leukemia, particularly low-hypodiploid ALL where 40% of children carry germline TP53 mutations 1, 2
- Other leukemias including acute myeloid leukemia and myelodysplastic syndrome 2, 4
- Lymphomas occur less frequently but are part of the broader spectrum 5, 4
Expanded Cancer Spectrum
Beyond the core cancers, carriers of TP53 pathogenic variants face increased risk for:
Carcinomas
- Lung adenocarcinoma, particularly in Brazilian p.R337H carriers but also in classic TP53 mutation carriers 1, 6
- Gastrointestinal tract cancers including gastric and colorectal carcinomas, occurring at earlier ages than in the general population 1, 7, 5
- Prostate cancer in male carriers 1
- Papillary thyroid cancer, especially in p.R337H carriers 1, 7
- Renal cancer 1, 7
Other Malignancies
- Melanoma and skin cancers 6, 7
- Ovarian cancer 7
- Pancreatic cancer 6
- Neuroblastoma (rare TP53 germline variants contribute to childhood cases) 1
Critical Clinical Features
Penetrance and Risk
- Nearly 100% lifetime cumulative cancer incidence in TP53 mutation carriers, with >90% in females and >70% in males 2, 7, 8
- Multiple primary malignancies are particularly common, with 23% of cancers in LFS families falling outside the six core tumor types but occurring at unusually early ages 5
- Secondary malignant neoplasms represent a major concern, especially following radiation therapy 1
Age-Specific Patterns
- Cancer risk before age 30 is approximately 50% in classic TP53 mutation carriers (15-20% in Brazilian p.R337H carriers) 1
- The median age of first cancer diagnosis is significantly younger than sporadic cases across all tumor types 5, 8
Important Clinical Caveats
The absence of family history does not exclude LFS, as de novo mutations occur and incomplete penetrance can obscure family patterns—80% of children with diffuse anaplastic rhabdomyosarcoma have TP53 mutations often without obvious family history 1, 6
The Brazilian p.R337H founder mutation demonstrates a somewhat attenuated phenotype with later onset and different tumor patterns (higher rates of thyroid, renal, and lung adenocarcinoma; later breast cancer onset at mean age 40 versus 32 years) compared to classic TP53 mutations 1
Radiation sensitivity is a critical consideration, as LFS patients are at markedly increased risk for radiation-induced secondary malignancies, necessitating preference for MRI over CT imaging and modification of treatment approaches (mastectomy over lumpectomy with radiation) 6, 7, 9