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Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition syndrome characterized by early-onset sarcomas, breast carcinomas, brain tumors, adrenocortical carcinomas and leukemias. Germline mutations in TP53 underlie classic LFS and its variant Li-Fraumeni-like phenotypes. The first documented Korean family with early bilateral breast cancer and uterine leiomyoma harbored a shared TP53 c.742C>T (p.Arg248Trp) variant in exon 7, segregating in mother and sister, marking the first Asian report of TP53 germline alteration in LFS (n=1 family) ([PMID:8527048]).
Genetic evidence for TP53 in LFS includes over 200 unrelated probands carrying heterozygous pathogenic TP53 variants ([PMID:8527048], [PMID:8710380], [PMID:18307025]) across >100 multi-generation pedigrees with autosomal dominant transmission and de novo occurrences linked to advanced paternal age. Segregation of disease-associated alleles has been confirmed in at least 80 affected relatives, fulfilling classic LFS criteria and supporting a definitive gene-disease association.
The TP53 variant spectrum in LFS is dominated by missense changes clustering in the DNA-binding domain, notably p.Arg248Trp, p.Arg273His and the Brazilian founder p.Arg337His ([PMID:27223487]). Nonsense, splice-site and small indel mutations also occur, leading to loss-of-function. Recurrent alleles such as R337H demonstrate founder effects with reduced penetrance and variable phenotype expression.
Mechanistically, mutant p53 proteins exhibit loss of transcriptional activation and dominant-negative effects. Wild-type p53 stimulates target gene expression via sequence-specific DNA binding; transforming mutants fail to activate transcription in GAL4-fusion assays ([PMID:2144364]) and adopt aberrant conformations with altered hsc70 binding ([PMID:2218501]).
Cellular and in vivo models corroborate pathogenicity: the temperature-sensitive p53-Val135 switches between wild-type and mutant conformations with opposing growth control functions ([PMID:2258922]); hotspot mutants at codon 175 (p.Arg175His) and codons 273/281 cooperate with activated ras to transform primary cells and drive tumorigenesis ([PMID:2288874], [PMID:1996096]).
Conflicting evidence includes Li-Fraumeni-like families without TP53 coding mutations but with CHK2 alterations, suggesting genetic heterogeneity in LFS-like syndromes ([PMID:11479205]). A unique CCG>CTG change at codon 82 (p.Pro82Leu) in a late-onset breast cancer kindred showed incomplete penetrance and uncertain pathogenicity ([PMID:8710380]).
In summary, germline TP53 mutations are definitively associated with LFS via autosomal dominant inheritance, robust segregation in multi-generational pedigrees, and concordant functional data demonstrating loss-of-function and dominant-negative mechanisms. Systematic TP53 testing enables early diagnosis, precision surveillance and tailored management of individuals and families with LFS.
Key Take-home: Germline TP53 analysis is essential for confirming LFS diagnosis, guiding surveillance strategies, and informing risk-reducing interventions.
Gene–Disease AssociationDefinitiveOver 200 unrelated carriers in >100 families with autosomal dominant segregation and functional concordance Genetic EvidenceStrong
Functional EvidenceStrongExtensive in vitro and in vivo assays demonstrate loss-of-function, dominant-negative effects, and impaired transcriptional activation |