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A 4-year-old is diagnosed with adrenocortical carcinoma. Her mother had breast cancer at 32 and her maternal grandmother died of a brain tumor at 40. A TP53 pathogenic variant is identified.
AD; TP53 (tumor suppressor, "guardian of the genome")
- ~70% inherited, ~30% de novo
Core Cancers (SBLA):
- Sarcoma (bone and soft tissue)
- Breast cancer (premenopausal)
- Leukemia/lymphoma
- Adrenal cortical carcinoma (childhood, highly associated)
- Brain tumors (especially choroid plexus carcinoma)
- Multiple primary cancers
- Very early onset
- Radiation sensitivity → avoid radiation when possible
- Lifetime cancer risk >90%
- Classic clinical criteria: a sarcoma before age 45, plus a first-degree relative with any cancer before age 45, plus a first- or second-degree relative with cancer before age 45 or a sarcoma at any age
- The broader Chompret criteria prompt TP53 testing for early-onset core cancers (sarcoma, breast, brain, adrenocortical), multiple primaries, childhood adrenocortical carcinoma, or choroid plexus carcinoma regardless of family history
- Confirm with germline TP53 testing; consider that an apparent germline variant can reflect clonal hematopoiesis or low-level mosaicism, which may need confirmation in a non-blood tissue
- Intensive surveillance (whole-body MRI, brain MRI, biochemical markers)
- Consider risk-reducing mastectomy
- Avoid radiation when possible
SBLA cancers in Li-Fraumeni: Sarcoma, Breast, Leukemia/lymphoma, Adrenal cortical carcinoma. "TP53 = The Protector, 53 kDa"
TP53 visual: "5" looks like an "S" (sarcoma), "3" looks like a sideways B (brain tumors, breast). TP = Tumor Protein, the guardian of the genome.