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Li-Fraumeni Syndrome

  • Author: ; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Mar 02, 2016
 

Background

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer.[1] Li-Fraumeni syndrome is characterized by the wide variety of cancer types seen in affected individuals, a young age at onset of malignancies, and the potential for multiple primary sites of cancer during the lifetime of affected individuals. The following are the criteria for classic Li-Fraumeni syndrome, Li-Fraumeni–like syndrome, and the Chompret criteria, which provide guidelines for consideration of TP53 genetic testing.

Classic Li-Fraumeni syndrome criteria are as follows[2] :

  • A proband diagnosed with a sarcoma before age 45 years and
  • A first-degree relative with any cancer diagnosed before age 45 years and
  • Another first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age

Li-Fraumeni–like syndrome criteria are as follows:

  • Birch definition [3] : (1) a proband with any childhood cancer or sarcoma, brain tumor, or adrenocortical carcinoma diagnosed before age 45 years and  (2) a first- or second-degree relative with a typical Li-Fraumeni cancer (sarcoma, breast cancer, brain tumor, adrenocortical carcinoma, or leukemia) at any age and (3) a first- or second-degree relative with any cancer before age 60 years
  • Eels definition [4] : Two first- or second-degree relatives with Li-Fraumeni–related malignancies (sarcoma, breast cancer, brain tumor, leukemia, adrenocortical tumor, melanoma, prostate cancer, pancreatic cancer) at any age

Chompret criteria for Li-Fraumeni syndrome are as follows:

  • A proband who has (1) a tumor belonging to the Li-Fraumeni tumor spectrum (soft-tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or bronchoalveolar lung cancer) before age 46 years and  (2) at least one first- or second-degree relative with a Li-Fraumeni tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors [5] or
  • A proband with multiple tumors (except multiple breast tumors), 2 of which belong to the Li-Fraumeni tumor spectrum and the first of which occurred before age 46 years [6] or
  • A proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history [7]

While most hereditary family cancer syndromes involve 1 or 2 specific tumor types, members of Li-Fraumeni syndrome kindreds are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft-tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma. Several other cancers have been seen at lower rates in Li-Fraumeni syndrome kindreds, including cancers of the lung, colorectum, stomach, prostate, ovary, and pancreas, as well as lymphoma, melanoma, and choroid plexus carcinoma.[8, 9]

Although osteosarcoma and chondrosarcomas occur frequently, no evidence suggests increased occurrence of Ewing sarcoma in association with Li-Fraumeni syndrome.

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Pathophysiology

Li-Fraumeni syndrome has been linked to germline mutations of the tumor suppressor gene TP53. Mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.[10] Approximately 70% of Li-Fraumeni syndrome kindreds and 40% of Li-Fraumeni–like families have germline mutations in the TP53 tumor suppressor gene.[11, 3] Over 767 germline mutations and 29, 881 somatic mutations have been identified in the TP53 gene.[1]

TP53, which is located on band 17p13.1, codes for a 53-kd nuclear protein transcription factor that has important regulatory control over cell proliferation and homeostasis, specifically the cell cycle, DNA repair processes, and apoptosis.

Somatic (nongermline) TP53 tumor suppressor gene mutations are common in sporadic human cancers, suggesting that TP53 alterations play an important role in the development of cancer. Moreover, a broad range of cell line and transgenic animal experiments show direct involvement of TP53 mutations in malignant transformation. Alterations of p53 function are the result of either loss of function of wild type p53, increased or aberrant protein function, or dominant negative effects of the mutated protein.

This impairment in p53 function is thought to lead to loss of protection against the accumulation of genetic alterations. p53 and the ubiquitin ligase HDM2 have been shown to interact with another E3 and E4 ubiquitin ligase UBE4B to induce the polyubiquitination and degradation of p53, which prevented apoptosis of medulloblastoma and ependymoma cells. Overexpression of UBE4B was also associated with amplification of its gene in brain tumors.[12]

These laboratory data support the hypothesis of constitutional mutations as the etiology of Li-Fraumeni syndrome. Although inactivation of TP53 confers a predisposition to cancer, this alone is not sufficient because not all families with classic Li-Fraumeni syndrome or Li-Fraumeni–like syndrome have detectable alterations of TP53. The absence of detectable germline TP53 mutations in some families suggests that other genes might be involved in the syndrome or that the p53 protein may undergo posttranslational alterations.

Specifics of the inherited TP53 mutation may have a significant effect on the cancer phenotype in the affected family. Most Li-Fraumeni syndrome–associated TP53 defects involve missense point mutations occurring in a hot-spot region of exons 5-8, a portion of the gene that codes for the core DNA-binding domain of the protein. Missense mutations lead to a stable but inactive protein, which accumulates in the nucleus of tumor cells. Frameshift, nonsense, and splice-site mutations can also be present, but do not lead to accumulation of p53 protein.

Kindreds with constitutional mutations in the hot spot region display more aggressive cancer phenotypes than patients with other TP53 mutations and those patients that appear to lack any heritable defect. Families with mutations in the hot spot region include those with younger probands at the time of cancer diagnosis. Mutations in exons 5-8 are also associated with a higher overall incidence in family members with breast cancer and CNS tumors diagnosed when patients are younger than 45 years, suggesting a higher rate of penetrance of the cancer phenotype in families with these types of inherited TP53 defects.

Single nucleotide polymorphisms in both TP53 and MDM2, an integral component of p53 function, appear to influence the age of cancer onset in Li-Fraumeni syndrome.[13, 14] Short telomeres are also associated with younger age of onset of first cancer in Li-Fraumeni syndrome families.[15, 16] Genomic copy number variation, used as a marker of genetic instability, is higher in patients with germline TP53 mutations than in healthy controls.[17]

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Epidemiology

 

Frequency

United States

Li-Fraumeni syndrome appears to be rare, with approximately 400 reported families described in the literature since it was first characterized in 1969; its actual population incidence is unknown. Each year, approximately 5-10 cases of soft-tissue sarcoma occur per 1 million children younger than 15 years. In a study of sarcoma patients, 10% of families with either an osteosarcoma diagnosed before age 20 years or a soft-tissue sarcoma diagnosed before age 16 years were found to have germline TP53 mutations.[18]

A study by Yurgelun et al examined the frequency of germline TP53 alterations in patients with early-onset colorectal cancer. The study found that out of the 457 eligible participants, 6 (1.3%) carried germline missense TP53 alterations, however, none of these TP53 alterations met the clinical criteria for Li-Fraumeni syndrome.[19]

Mortality/Morbidity

The cancers that occur most commonly in members of Li-Fraumeni syndrome kindreds are breast cancer, brain tumors, acute leukemia, soft-tissue sarcomas, osteosarcoma, and adrenal cortical carcinoma. Individuals with Li-Fraumeni syndrome have a lifetime cancer risk that approaches 100% by age 70 years.[20] More than half of all tumors occur before age 30 years.[21] Patients with Li-Fraumeni syndrome can be successfully treated for the initial cancer, however, radiation therapy is avoided, when possible, due to several case reports and preclinical evidence demonstrating an increased risk in radiation-induced cancers in these patients.[22, 23]  Furthermore, Li-Fraumeni patients are at significant risk for the development of a second primary malignancy[24] .  

Race

No evidence suggests either an ethnic predisposition for Li-Fraumeni syndrome or an increased or decreased frequency based on nationality.

Sex

Li-Fraumeni syndrome has an autosomal dominant inheritance pattern; therefore, the genetic predisposition for cancer equally affects males and females. Cancer penetrance is 93% for female carriers compared with 73% for male carriers, owing to the increased risk of breast cancer in females.[20] It is estimated that 5-8% of women diagnosed with early-onset breast cancer (at < 30 y) with a negative family history may have a mutation in the TP53 gene.[25]

Almost 90% of affected females develop breast cancer by age 60 years, with a majority occurring before age 45 years.[26] Increased occurrence of breast cancer in males of Li-Fraumeni syndrome kindreds is not reported.

Age

Although approximately 10% of cancers occur in individuals younger than 45 years in the general population, more than half of the cancers occur in Li-Fraumeni syndrome family members younger than 45 years.

The risk for developing soft-tissue sarcomas is greatest before age 10 years. Brain cancer also appears early in childhood, with a second peak in the fourth to fifth decade of life. Osteosarcoma risk peaks during adolescence. Breast cancer risk for females with Li-Fraumeni syndrome increases significantly at around age 20 years and continues to increase in adulthood.[20]

Bougeard et al updated the clinical presentation of 1,730 French patients suggestive of LFS by identifying 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations. The study found that in children, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS). In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients.[27]

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Contributor Information and Disclosures
Author

 

Disclosure: Nothing to disclose.

Coauthor(s)

Kathleen M Sakamoto, MD, PhD Shelagh Galligan Professor, Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine

Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: International Society for Experimental Hematology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Timothy P Cripe, MD, PhD, FAAP Chief, Division of Hematology/Oncology/BMT, Gordon Teter Endowed Chair in Pediatric Cancer, Nationwide Children's Hospital; Professor of Pediatrics, Ohio State University College of Medicine

Timothy P Cripe, MD, PhD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Association for Cancer Research, American Pediatric Society, American Society of Gene and Cell Therapy, American Society of Pediatric Hematology/Oncology, Connective Tissue Oncology Society, Society for Pediatric Research, Children's Oncology Group

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Stephan A Grupp, MD, PhD Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania School of Medicine

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Katharine E Brock, MD Fellow, Pediatric Hematology and Oncology, Lucile Packard Children’s Hospital, Stanford University School of Medicine

Katharine E Brock, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, American Society of Clinical Oncology, Society for Simulation in Healthcare

Disclosure: Nothing to disclose.

Acknowledgements

Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Kavita Patel, MD Assistant Professor of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine

Kavita Patel, MD is a member of the following medical societies: American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

References
  1. International Agency for Research on Cancer. IARC TP53 Database. Available at http://p53.iarc.fr/. Accessed: February 18, 2016.

  2. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988 Sep 15. 48(18):5358-62. [Medline].

  3. 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 Res. 1994 Mar 1. 54(5):1298-304. [Medline].

  4. Eeles RA. Germline mutations in the TP53 gene. Cancer Surv. 1995. 25:101-24. [Medline].

  5. Chompret A, Abel A, Stoppa-Lyonnet D, Brugiéres L, Pagés S, Feunteun J, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet. 2001 Jan. 38(1):43-7. [Medline]. [Full Text].

  6. 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. J Clin Oncol. 2009 Sep 10. 27(26):e108-9; author reply e110. [Medline].

  7. 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. J Med Genet. 2008 Aug. 45(8):535-8. [Medline].

  8. 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. [Medline]. [Full Text].

  9. 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. J Clin Oncol. 2009 Mar 10. 27(8):1250-6. [Medline].

  10. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990 Nov 30. 250(4985):1233-8. [Medline].

  11. Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res. 1997 Aug 1. 57(15):3245-52. [Medline].

  12. Wu H, Pomeroy SL, Ferreira M, Teider N, Mariani J, Nakayama KI, et al. UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. Nat Med. 2011 Mar. 17(3):347-55. [Medline].

  13. Marcel V, Palmero EI, Falagan-Lotsch P, Martel-Planche G, Ashton-Prolla P, Olivier M, et al. TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. J Med Genet. 2009 Nov. 46(11):766-72. [Medline].

  14. Renaux-Petel M, Sesboüé R, Baert-Desurmont S, Vasseur S, Fourneaux S, Bessenay E, et al. The MDM2 285G-309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome. Fam Cancer. 2013 Jul 25. [Medline].

  15. Tabori U, Nanda S, Druker H, Lees J, Malkin D. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. 2007 Feb 15. 67(4):1415-8. [Medline].

  16. Trkova M, Prochazkova K, Krutilkova V, Sumerauer D, Sedlacek Z. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007 Aug 1. 110(3):694-702. [Medline].

  17. Shlien A, Tabori U, Marshall CR, et al. Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci U S A. 2008 Aug 12. 105(32):11264-9. [Medline].

  18. 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 Aug. 51(2):344-56. [Medline]. [Full Text].

  19. Yurgelun MB, Masciari S, Joshi VA, Mercado RC, Lindor NM, Gallinger S, et al. Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry. JAMA Oncol. 2015 May. 1 (2):214-21. [Medline].

  20. Mai PL, Malkin D, Garber JE, Schiffman JD, Weitzel JN, Strong LC, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 2012 Oct. 205(10):479-87. [Medline]. [Full Text].

  21. Le Bihan C, Moutou C, Brugieres L, Feunteun J, Bonaiti-Pellie C. ARCAD: a method for estimating age-dependent disease risk associated with mutation carrier status from family data. Genet Epidemiol. 1995. 12(1):13-25. [Medline].

  22. Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer. 2001 Aug 20. 96 (4):238-42. [Medline].

  23. Heymann S, Delaloge S, Rahal A, Caron O, Frebourg T, Barreau L, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol. 2010 Nov 8. 5:104. [Medline].

  24. Boyle JM, Spreadborough A, Greaves MJ, Birch JM, Varley JM, Scott D. The relationship between radiation-induced G(1)arrest and chromosome aberrations in Li-Fraumeni fibroblasts with or without germline TP53 mutations. Br J Cancer. 2001 Jul 20. 85 (2):293-6. [Medline].

  25. 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?. Fam Cancer. 2012 Dec. 11(4):607-13. [Medline].

  26. Allain DC. Genetic counseling and testing for common hereditary breast cancer syndromes: a paper from the 2007 William Beaumont hospital symposium on molecular pathology. J Mol Diagn. 2008 Sep. 10(5):383-95. [Medline].

  27. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015 Jul 20. 33 (21):2345-52. [Medline].

  28. Birch JM, Blair V, Kelsey AM, et al. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene. 1998 Sep 3. 17(9):1061-8. [Medline].

  29. Birch JM, Hartley AL, Marsden HB, et al. Excess risk of breast cancer in the mothers of children with soft tissue sarcomas. Br J Cancer. 1984 Mar. 49(3):325-31. [Medline].

  30. Curtin K, Smith KR, Fraser A, Pimentel R, Kohlmann W, Schiffman JD. Familial risk of childhood cancer and tumors in the li-fraumeni spectrum in the utah population database: Implications for genetic evaluation in pediatric practice. Int J Cancer. 2013 Nov 15. 133(10):2444-53. [Medline].

  31. [Guideline] National Comprehensive Cancer Network. NCCN Guidelines: Li-Fraumeni Syndrome. Available at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed: February 18, 2016.

  32. Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011 Jun. 12(6):559-67. [Medline].

  33. Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF Jr. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer. 2005 Jun 1. 103(11):2391-6. [Medline].

  34. Hisada M, Garber JE, Fung CY, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998 Apr 15. 90(8):606-11. [Medline].

  35. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?. Ann Intern Med. 1969 Oct. 71(4):747-52. [Medline].

  36. Li FP, Garber JE, Friend SH, et al. Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. J Natl Cancer Inst. 1992 Aug 5. 84(15):1156-60. [Medline].

  37. Peterson SK, Pentz RD, Blanco AM, et al. Evaluation of a decision aid for families considering p53 genetic counseling and testing. Genet Med. 2006 Apr. 8(4):226-33. [Medline].

 
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