Li-Fraumeni Syndrome

Li-Fraumeni (TP53) Sequencing and Deletion/Duplication 2009313
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Most comprehensive test for LFS

Li-Fraumeni (TP53) Sequencing 2009302
Method: Polymerase Chain Reaction/Sequencing

Appropriate initial test for LFS

Related Test
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing in known

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer predisposition syndrome caused by germline variants in the tumor suppressor gene, TP53. Individuals with  germline pathogenic variants in TP53 have a greatly increased risk of developing cancer, often as children or young adults. Tumors most often associated with LFS include breast, osteosarcoma, rhabdomyosarcoma, brain tumors, leukemias, and adrenocortical carcinoma. Germline variants in TP53 are found in approximately 80% of classic LFS cases.

Disease Overview

Prevalence

1/5,000-20,000 

Age of Onset

Varies by cancer type

Symptoms

  • Predisposition to early-onset and multiple primary cancers:
    • 50% penetrance by age 30
    • 90% penetrance by age 60
  • Classic LFS-related cancers:
    • Bone and soft tissue sarcomas
    • Breast cancer (especially premenopausal)
    • Brain tumors (especially choroid plexus)
    • Adrenocortical carcinoma
  • Other LFS cancers:
    • Leukemia/lymphoma
    • Lung
    • Colorectal/gastrointestinal
    • Renal cell and other genitourinary
    • Skin
    • Nonmedullary thyroid
    • Early childhood tumors

Diagnostic Issues

TP53 gene variants are common in tumor tissue

  • Presence of TP53 pathogenic variant(s) in tumor does not necessarily imply LFS or Li-Fraumeni-like (LFL) syndrome
  • Germline testing is needed to differentiate somatic from constitutional TP53 gene variant(s)
    • For individuals with an active hematological malignancy, testing on cultured fibroblasts or buccal specimen is required for accurate interpretation of test results

Diagnostic Criteria

  • Classic criteria for LFS :
    • Sarcoma diagnosed at <45 years
    • And first-degree relative with cancer <45 years
    • And another first- or second-degree relative with any cancer <45 years or sarcoma at any age
  • Chompret criteria :
    • Individual with LFS-related cancer <46 years AND at least one first- or second-degree relative with LFS-related cancer<56 years (except breast cancer if proband has breast cancer) or with multiple primary cancers at any age
    • Individual with at least two LFS-related primary tumors (except multiple breast tumors) first diagnosed <46 years
    • Individual with adrenocortical carcinoma or choroid plexus tumor, regardless of family history

Genetics

Gene

TP53

Inheritance

Autosomal dominant

Penetrance

High (age dependent):

  • 50% penetrance by age 30 
  • 90% penetrance by age 60 

Structure/Function

TP53 codes for p53 protein:

  • Important tumor suppressor
  • Involved in regulation of cell growth, DNA repair, and apoptosis

Variants

  • Mostly missense
  • Some small deletions and splice site
  • Large deletions/duplications are rare
  • De novo variants: 7-20% of variants 

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity:
    • ~80% of individuals with classic LFS criteria have a detectable TP53 variant  
      • ~95% of TP53 pathogenic variants are sequencing variants; ~1% are large deletions/duplications  
  • Analytical sensitivity/specificity: >95%

Results

  • Positive: onepathogenic TP53 variant detected
    • Individual predicted to be affected with LFS
    • At risk for developing LFS-related cancers
  • Negative: no pathogenic TP53 variant detected
    • Risk for LFS is significantly reduced but not eliminated
  • Inconclusive: variant of uncertain clinical significance detected

Limitations

  • Not determined or evaluated:
    • Regulatory region variants
    • Deep intronic variants
    • Breakpoints of large deletions/duplications
  • Diagnostic errors can occur due to rare sequence variations
  • Individuals with hematological malignancies and/or previous allogenic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen
    • Testing on cultured fibroblasts or buccal specimen is required for accurate interpretation of test results
References 
  1. Schneider K, Zelley K, Nichols K, Garber J. Li-Fraumeni Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Updated: Apr 2013; Accessed: Jul 2019]
  2. Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988; 48(18): 5358-62. PubMed
  3. Chompret A, Abel A, Stoppa-Lyonnet D, Brugiéres L, Pagés S, Feunteun J, Bonaïti-Pellié C. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001; 38(1): 43-7. PubMed
  4. Lustbader ED, Williams WR, Bondy ML, Strom S, Strong LC. Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients. Am J Hum Genet. 1992; 51(2): 344-56. PubMed
  5. Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009; 46(10): 689-93. PubMed
  6. Malkin D. Li-fraumeni syndrome. Genes Cancer. 2011; 2(4): 475-84. PubMed

Last Update: September 2019