Li-Fraumeni Syndrome

A(z) condition ismertetése

A rare inherited cancer predisposition, usually caused by variants in TP53, with a very high lifetime risk of cancer, often at a young age. Typical cancers include sarcomas, breast cancer, brain tumours, adrenocortical carcinoma and leukaemia.

Li-Fraumeni Syndrome is caused by germline pathogenic variants in TP53, the gene encoding p53, the 'guardian of the genome.' TP53 normally responds to DNA damage by halting cell division, activating repair, or triggering apoptosis if damage is irreparable. When inherited as a pathogenic variant, one copy is lost. This follows Knudson's two-hit tumor suppressor model: a single somatic mutation in the remaining copy removes all p53 function, eliminating the critical brake on damaged cell proliferation. The result is a syndrome of strikingly early-onset, multiple independent primary cancers.

Li-Fraumeni Syndrome affects approximately 1 in 5,000-20,000 individuals, though prevalence is likely underestimated due to variable family histories and de novo variants (7 to 20% of cases). The five core cancers are soft-tissue sarcomas, osteosarcomas, brain tumors, premenopausal breast cancer, and adrenocortical carcinomas, but the spectrum extends to virtually every tissue type. Lifetime cancer risk approaches 100% in females and ~75% in males by age 70. Many affected individuals develop multiple independent primary cancers over a lifetime, sometimes before age 40.

A confirmed TP53 variant diagnosis enables the Toronto Protocol: a comprehensive surveillance program including annual whole-body MRI, brain MRI, breast MRI from age 20, and abdominal ultrasound. This surveillance detects early-stage cancers when outcomes are best, improving overall survival significantly. Critically, radiation exposure must be minimized: TP53-deficient cells are hypersensitive to radiation-induced secondary cancers, making CT scans and radiation therapy particularly dangerous. Cascade testing of first-degree relatives, including children, identifies others at risk before symptoms develop.

TP53 pathogenic variants are predominantly missense mutations in the DNA-binding domain, but include truncating variants, splice-site variants, and whole-gene deletions, each with potential genotype-phenotype distinctions that affect surveillance intensity.

A vizsgált betegség

Miért a teljes genom szekvenálás

Standard panels may miss TP53 variants entirely, or detect somatic variants in clonal hematopoiesis that mimic germline findings, requiring tissue discrimination standard sequencing cannot provide.

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