LI-FRAUMENI SYNDROME

Li-Fraumeni syndrome is a highly penetrant, yet rare, condition that predisposes to many tumors. Tumors and cancers frequently occur in childhood, but can also be seen throughout adulthood.

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Li-Fraumeni syndrome is a highly penetrant, yet rare, condition that predisposes to many tumors. Tumors and cancers frequently occur in childhood, but can also be seen throughout adulthood.

Disease Name 
Li-Fraumeni syndrome
Disease Information 

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome that can affect both children and adults. It is estimated to occur in up to 1/20,000 people worldwide.1 LFS is characterized by a broad spectrum of tumor types, including the following “core” cancers: sarcoma (osteosarcoma, or soft tissue), pre-menopausal breast cancer, brain tumors (such as astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinomas), and adrenocortical carcinoma (ACC).1-3 LFS is caused by germline mutations in the TP53 tumor suppressor gene, which encodes the p53 protein that activates numerous genes involved in cell cycle arrest, DNA repair, and apoptosis when damaged DNA is present. 

Individuals with TP53 mutations have a 21-49% risk of developing cancer by age 30, and a lifetime risk of up to 68-93%.5 Lifetime cancer risks for women with TP53 mutations are significantly higher than male mutation carriers (due to the increased risk of breast cancer), and the risk of multiple primary cancers is increased for both genders.6-8 Mutations in TP53 are inherited in an autosomal dominant manner, though an estimated 7-20% of affected individuals have a de novo mutation.1

Testing Benefits & Indication 

Genetic testing is useful to:

  • Confirm a diagnosis in individuals who are clinically suspicious for LFS, to avoid any unnecessary testing and procedures
  • Diagnose a personal and/or family history suggestive of hereditary breast cancer.  These individuals may have previously tested negative for BRCA1/2 mutations or may be considering BRCA genetic testing.
  • Diagnose patients with childhood-onset cancers (particularly ACC and choroid plexus carcinoma)
  • Provide appropriate screening recommendations and risk-reducing options for TP53 mutation-positive patients and their relatives

Indications for TP53 genetic testing include the following:

 
   
Classic LFS criteria
  • Bone or soft tissue sarcoma diagnosed <45 y/o AND;
  • A first-degree relative (FDR) diagnosed with cancer <45 y/o AND; 
  • FDR or second-degree relative (SDR) diagnosed with any type of cancer <45 y/o or sarcoma at any age
Chompret criteria*
  • Proband with a tumor diagnosed <age 46 belonging to the LFS spectrum, with at least one FDR or SDR with a LFS tumor (at least one of these tumors must not be breast) diagnosed <age 56, or with multiple tumors at any age OR;
  • Proband with multiple tumors, of which at least two belong to the LFS spectrum (excluding multiple breast cancers) and at least one diagnosed <age 46  OR;
  • Proband with ACC or choroid plexus carcinoma at ANY AGE of onset
Other^
  • Personal history of breast cancer diagnosed < age 31

*Up to 36% of patients that meet the Chompret criteria will be found to carry a TP53 mutation:1,4,9-10
^It has been estimated that 5-8% of women will haveTP53 mutations with breast cancer diagnosed before age 30, even with a negative family history.1,9-11

Test Description 

TP53 coding exons 1-10 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-10. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by incorporating the gDNA onto a microfluidics chip, along with primer pairs followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.12  Gross deletion/duplication analysis of TP53 using the multiplex ligation-dependent probe amplification (MLPA) kit is also performed.

Mutation Detection Rate 

Detectable mutations in TP53 can account for ~80% of LFS cases (clinical sensitivity). Ambry's TP53 analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Of note, somatic mutations in the TP53 gene are a common occurrence across a wide variety of tumor types. It is expected that the DNA isolated from provided peripheral blood and saliva samples would be representative of an individual's germline DNA; however, the assays offered here cannot definitively determine whether identified TP53 alterations are of somatic or germline origin. 

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
2866 TP53 Sequence and Deletion/Duplication 10-21
2862 TP53 Specific Site Analysis  7-14

 

Specialty 
Genes 
TP53
References 
  1. Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families With p53 Germline Mutations. Journal of Clinical Oncology. 2009;27(8):1250-6.
  2. Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, et al. Prevalence and Diversity of Constitutional Mutations in the p53 Gene among 21 Li-Fraumeni Families. Cancer Research. 1994;54(5):1298-304.
  3. Li FP, et al. A cancer family syndrome in twenty-four kindreds. Cancer Research. 1988; 48: 5358-5362.
  4. Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, et al. Li-Fraumeni and Related Syndromes: Correlation between Tumor Type, Family Structure, and TP53 Genotype. Cancer Research. 2003;63(20):6643-50.
  5. Hwang SJ, Lozano G, Amos CI, Strong LC. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003 Apr;72(4):975-83. Epub 2003 Feb 27.
  6. Wu CC, Shete S, Amos CI, Strong LC. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res. 2006 Aug 15;66(16):8287-92.
  7. Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998 Apr 15;90(8):606-11.
  8. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaïti-Pellié C, Tinat J, Baert-Desurmont S, Frebourg T. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015 Jul 20;33(21):2345-52. doi: 10.1200/JCO.2014.59.5728. Epub 2015 May 26.
  9. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, et al. 2009 Version of the Chompret Criteria for Li Fraumeni Syndrome. Journal of Clinical Oncology. 2009;27(26):e108-e9.
  10. Bougeard G, Sesboüé R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, et al. Molecular basis of the Li–Fraumeni syndrome: an update from the French LFS families. Journal of Medical Genetics. 2008;45(8):535-8.
  11. McCuaig JM, Armel SR, Novokmet A, Ginsburg OM, Demsky R, Narod SA, et al. Routine TP53 testing for breast cancer under age 30: ready for prime time? Familial cancer. 2012;11(4):607-13. doi: 10.1007/s10689-012-9557-z.
  12. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.