What mutations cause Li-Fraumeni syndrome?

Li-Fraumeni Syndrome is Caused by TP53 Gene Mutations

Li-Fraumeni syndrome (LFS) is caused by germline mutations in the TP53 tumor suppressor gene. 1 This is the only gene definitively associated with this rare hereditary cancer predisposition syndrome.

Genetic Basis of Li-Fraumeni Syndrome

• TP53 is located on chromosome 17 and encodes the p53 protein, which functions as a transcription factor that binds directly to DNA and plays crucial roles in controlling cell cycle and apoptosis 1
• The p53 protein is activated in response to various cellular stressors and controls the expression of multiple genes crucial for tumor suppression 1
• Germline mutations in the TP53 gene have been observed in over 50% (and in over 70% in some studies) of families meeting the classic definition of LFS 1
• No other gene mutations have been associated with LFS to date 2

Types of TP53 Mutations in Li-Fraumeni Syndrome

• Missense mutations are the most common type, occurring in approximately 70% of cases, most frequently altering residues within the DNA-binding domain 1
• Other alterations include splicing defects, intragenic deletions, frameshift mutations, nonsense mutations, in-frame insertions/deletions, and intronic mutations 1
• Twenty percent of LFS families harbor one of six hotspot mutations (p.R175H, p.G245S, p.R248Q, p.R248W, p.R273H, and p.R282W) 1
• The rate of de novo mutations could be as high as 25% 1

Genotype-Phenotype Correlations

• The type of TP53 mutation and its effect on p53 function may influence disease penetrance, cancer site, and risk of secondary malignancies 1
• Dominant-negative TP53 missense mutations within the DNA-binding domain are associated with the highest cancer risk 1
• These dominant-negative mutations are commonly detected in LFS patients with brain tumors (62%), osteosarcoma (40%), and rhabdomyosarcoma (36%) 1
• Non-dominant-negative TP53 mutations occur more frequently in patients with adrenocortical carcinoma (76%) 1

Special Case: Brazilian Founder Mutation

• In Brazil, a specific founder mutation (c.1010G>A; p.R337H) is present in 0.3% of individuals from the South/Southeastern regions 1
• This mutation results in a variant form of LFS with some distinct characteristics:
  • Lower penetrance of cancer before age 30 (15-20% compared to 50% in carriers of classic mutations) 1
  • Later onset of adult tumors (e.g., breast cancers occur at a mean age of 40 years versus 32 years in classic carriers) 1
  • Higher occurrence of young adult papillary thyroid cancer, renal cancer, and lung adenocarcinoma compared to carriers of other TP53 mutations 1

Genetic Modifiers

• Several genetic modifiers may influence the LFS phenotype, including:
  • MDM2 polymorphism rs2279744 1
  • TP53 polymorphisms, such as a duplication within intron 3 (PIN3) 1
  • Telomere length 1
  • Differential methylation or variant alleles in miRNAs that modify p53-mediated cell regulation 1
  • Accumulation of copy number variations (CNVs) 1

Clinical Implications

• Genetic testing for TP53 mutations is the definitive diagnostic method for confirming LFS 2
• TP53 mutations are considered biomarkers associated with the tumor spectrum of LFS 2
• Understanding the specific mutation can help guide surveillance strategies, as different mutations may be associated with different cancer risks and age of onset 1

Important Considerations for Genetic Testing

• Genetic testing should be offered to individuals meeting the Chompret criteria, which has shown the highest sensitivity (92%) for detecting TP53 mutations 3
• Testing should also be considered for children with sarcoma and young adults with breast cancer before age 30, even if they don't meet other criteria 3
• Approximately 70% of families with clinical features of LFS have detectable TP53 mutations 4

The identification of a TP53 mutation has significant implications for cancer surveillance and management strategies, as individuals with LFS have a nearly 100% lifetime risk of developing cancer 1.